8-hydroxy-1-oxo-tetrahydropyrrolopyrazine compounds useful as hiv integrase inhibitors

ABSTRACT

8-Hydroxy-1-oxo-tetrahydropyrrolopyrazine compounds are inhibitors of HIV integrase and inhibitors of HIV replication. More particularly, the compounds are of Formula (1): wherein R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are defined herein. The compounds are useful in the prevention and treatment of infection by HIV and in the prevention, delay in the onset, and treatment of AIDS. The compounds are employed against HIV infection and AIDS as compounds per se or in the form of pharmaceutically acceptable salts. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of preventing, treating or delaying the onset of AIDS and methods of preventing or treating infection by HIV are described.

This application claims the benefit of U.S. Provisional Application No.60/409,745, filed Sep. 11, 2002, the disclosure of which is herebyincorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention is directed to8-hydroxy-1-oxo-tetrahydropyrrolopyrazine compounds and pharmaceuticallyacceptable salts thereof, their synthesis, and their use as inhibitorsof the HIV integrase enzyme. The compounds of the present invention andtheir pharmaceutically acceptable salts are useful for preventing ortreating infection by HIV and for treating, delaying the onset of, orpreventing AIDS.

BACKGROUND OF THE INVENTION

A retrovirus designated human immunodeficiency virus (HIV) is theetiological agent of the complex disease that includes progressivedestruction of the immune system (acquired immune deficiency syndrome;AIDS) and degeneration of the central and peripheral nervous system.This virus was previously known as LAV, HTLV-III, or ARV. A commonfeature of retrovirus replication is the insertion by virally-encodedintegrase of proviral DNA into the host cell genome, a required step inHIV replication in human T-lymphoid and monocytoid cells. Integration isbelieved to be mediated by integrase in three steps: assembly of astable nucleoprotein complex with viral DNA sequences; cleavage of twonucleotides from the 3′ termini of the linear proviral DNA; covalentjoining of the recessed 3′ OH termini of the proviral DNA at a staggeredcut made at the host target site. The fourth step in the process, repairsynthesis of the resultant gap, may be accomplished by cellular enzymes.

Nucleotide sequencing of HIV shows the presence of a pol gene in oneopen reading frame (Ratner et al., Nature 1985, 313: 277]. Amino acidsequence homology provides evidence that the pol sequence encodesreverse transcriptase, integrase and an HIV protease [Toh et al., EMBOJ. 1985, 4: 1267; Power et al., Science 1986, 231: 1567; Pearj et al.,Nature 1987, 329: 351]. All three enzymes have been shown to beessential for the replication of HIV.

It is known that some antiviral compounds which act as inhibitors of HIVreplication are effective agents in the treatment of AIDS and similardiseases, including reverse transcriptase inhibitors such asazidothymidine (AZT) and efavirenz and protease inhibitors such asindinavir and nelfinavir. The compounds of this invention are inhibitorsof HIV integrase and inhibitors of HIV replication. The inhibition ofintegrase in vitro and of HIV replication in cells is a direct result ofinhibiting the strand transfer reaction catalyzed by the recombinantintegrase in vitro in HIV infected cells. A particular advantage of thepresent invention is highly specific inhibition of HIV integrase and HIVreplication.

The following references are of interest as background:

Chemical Abstracts No. 33-2525 discloses the preparation of5-chloro-8-hydroxy-1,6-naphthyridine-7-carboxylic acid amide from thecorresponding methyl ester.

U.S. Pat. No. 5,294,620 discloses certain 1,6-naphthyridine-2-onederivatives having angiotensin II antagonist activity.

US 2003/0055071 (Publication of U.S. application Ser. No. 09/973,853,filed Oct. 10, 2001) and WO 02/30930 (Publication of InternationalApplication No. PCT/US 01/31456, filed Oct. 9, 2001) each disclosecertain 8-hydroxy-1,6-naphthyridine-7-carboxamides as HIV integraseinhibitors, wherein the carboxamido nitrogen is directly or indirectlyattached to phenyl or phenyl fused to a carbocycle. The carboxamides aredisclosed to be useful, inter alia, for treating HIV infection andAIDS-WO 02/30426 discloses another group of8-hydroxy-1,6-naphthyridine-7-carboxamides as HIV integrase inhibitors,wherein the carboxamido nitrogen is directly or indirectly attached to aheterocycle. WO 02/055079 discloses still another group of8-hydroxy-1,6-naphthyridine-7-carboxamides as HIV integrase inhibitors,wherein the carboxamido nitrogen is part of a heterocyclic ring system.

WO 02/036734 discloses certain aza- and polyaza-naphthalenyl ketones tobe HIV integrase inhibitors. The ketones include certain1-aryl-1-(poly)azanaphthylenyl methanones and1-heterocyclyl-1-(poly)azanaphthylenyl methanones. Quinolinyl,naphthyridinyl, and quinoxalinyl are disclosed as suitable(poly)azanaphthylenyl groups in the ketones.

WO 03/35076 discloses certain 5,6-dihydroxypyrimidine-4-carboxamides asHIV integrase inhibitors, and WO 03/35077 discloses certainN-substituted 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamides asHIV integrase inhibitors.

SUMMARY OF THE INVENTION

The present invention is directed to novel8-hydroxy-1-oxo-tetrahydropyrrolopyrazine compounds. These compounds andtheir pharmaceutically acceptable salts are useful in the inhibition ofHIV integrase, the prevention of infection by HIV, the treatment ofinfection by HIV and in the prevention, treatment, and delay in theonset of AIDS, either as compounds or their pharmaceutically acceptablesalts, or as pharmaceutical composition ingredients, whether or not incombination with other HIV/AIDS antivirals, anti-infectives,immunomodulators, antibiotics or vaccines. More particularly, thepresent invention includes a compound of Formula (I), or apharmaceutically acceptable salt thereof:

wherein

R¹ is —H, —C₁₋₆ alkyl, —C₃₋₆ cycloalkyl, or —C₁₋₆ alkyl which issubstituted with 1 or 2 substituents each of which is independently:

-   -   (1) C₃₋₈ cycloalkyl,    -   (2) aryl,    -   (3) a 5- or 6-membered saturated or mono-unsaturated        heterocyclic ring containing from 1 to 4 heteroatoms        independently selected from N, O and S,    -   (4) a 5- or 6-membered heteroaromatic ring containing from 1 to        4 heteroatoms independently selected from N, O and S, or    -   (5) a 9- or 10-membered fused bicyclic heterocycle containing        from 1 to 4 heteroatoms independently selected from N, O and S,        wherein at least one of the rings is aromatic;    -   wherein    -   (A) each cycloalkyl is optionally substituted with from 1 to 3        substituents, each of which is independently halo, —C₁₋₆ alkyl,        or —O—C₁₋₆ alkyl;    -   (B) each aryl is optionally substituted with from 1 to 5        substituents each of which is independently        -   (1) —C₁₋₆ alkyl, optionally substituted with from 1 to 3            substituents each of which is independently —OH , —O—C₁₋₆            alkyl, —O—C₁₋₆ haloalkyl, —CN, —NO₂, —N(R^(a)R^(b)),            —C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(c), S(O)_(n)R^(c),            —SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(c),            —N(R^(a))SO₂R^(c), —N(R^(a))SO₂N(R^(a)R^(b)),            —OC(═O)N(R^(a)R^(b)), or —N(R^(a))C(═O)N(R^(a)R^(b)),        -   (2) —O—C₁₋₆ alkyl, optionally substituted with from 1 to 3            substituents each of which is independently —OH, —O—C₁₋₆            alkyl, —O—C₁₋₆ haloalkyl, —S(O)_(n)R^(c),            —C(═O)N(R^(a)R^(b)), —SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b),            —N(R^(a))CO₂R^(c), —N(R^(a))SO₂R^(c),            —N(R^(a))SO₂N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)), or            —N(R^(a))C(═O)N(R^(a)R^(b)),        -   (3) —C₁₋₆ haloalkyl,        -   (4) —O—C₁₋₆ haloalkyl,        -   (5) —OH,        -   (6) halo,        -   (7) —CN,        -   (8) —NO₂,        -   (9) —N(R^(a)R^(b)),        -   (10) —C(═O)N(R^(a)R^(b)),        -   (11) —C(═O)R^(a),        -   (12) —CO₂R^(c),        -   (13) —SR^(c),        -   (14) —S(═O)R^(c),        -   (15) —SO₂R^(c),        -   (16) —N(R^(a))SO₂R^(c),        -   (17) —SO₂N(R^(a)R^(b)),        -   (18) —N(R^(a))C(═O)R^(b), or        -   (19) —N(R^(a))CO₂R^(c);    -   (C) each saturated or mono-unsaturated heterocyclic ring is        -   (i) optionally substituted with from 1 to 5 substituents            each of which is independently halogen, —C₁₋₆ alkyl, —C₁₋₆            haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or oxo; and        -   (ii) optionally substituted with 1 or 2 substituents each of            which is independently aryl or a 5- or 6-membered            heteroaromatic ring containing from 1 to 4 heteroatoms            independently selected from N, O and S; and    -   (D) each heteroaromatic ring or each fused bicyclic heterocycle        is        -   (i) optionally substituted with from 1 to 7 substituents            each of which is independently halogen, —C₁₋₆ allyl, —C₁₋₆            haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or oxo; and        -   (ii) optionally substituted with 1 or 2 substituents each of            which is independently aryl or —C₁₋₆ alkyl;

R² is —H or —C₁₋₆ alkyl;

R³ is —H, —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, or —C₁₋₆ alkyl substituted withone of —OH, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —CN, —NO₂, —N(R^(a)R^(b)),—C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(c), —S(O)_(n)R^(c),—SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(c),—N(R^(a))SO₂R^(c), —N(R^(a))SO₂N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)), or—N(R^(a))C(═O)N(R^(a)R^(b));

R⁴ is:

-   -   (1) —H,    -   (2) —C₁₋₆ alkyl optionally substituted with one of —OH, —O—C₁₋₆        alkyl, —O—C₁₋₆ haloalkyl, —CN, —NO₂, —N(R^(a) ^(b)),        —C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(c), —S(O)_(n)R^(c),        —SO₂N(R^(a) ^(b)), —N(R^(a))—C(R^(b))═O, —N(R^(a))SO₂R^(c),        —N(R^(a))SO₂N(R^(a)R^(b)), —OC(═O)N(R^(a) ^(b)),        —N(R^(a))C(═O)N(R^(a)R^(b)), —O—C₁₋₆ alkyl-C(═O)N(R^(a)R^(b)),        —S—C₁₋₆ alkyl-C(═O)N(R^(a)R^(b)), —N(R^(a))—C₁₋₆        alkyl-C(═O)N(R^(a)R^(b)), or —N(SO₂R^(c))—C₁₋₆        alkyl-C(═O)N(R^(a)R^(b)),    -   (3) —C₁₋₆ haloalkyl,    -   (4) —C(═O)R^(a),    -   (5) —CO₂R^(c),    -   (6) —C(═O)N(R^(a)R^(b)),    -   (7) —SO₂N(R^(a)R^(b)),    -   (8) —C₂₋₆ alkenyl,    -   (9) —C₂₋₆ alkenyl-C(═O)—N(R^(a))₂,    -   (10) —C₂₋₅ alkynyl,    -   (11) —C₂₋₅ alkynyl-CH₂N(R^(a))₂,    -   (12) —C₂₋₅ alkynyl-CH₂OR^(a),    -   (13) —C₂₋₅ alkynyl-CH₂S(O)_(n)R^(c), or    -   (14) —R^(k),    -   (15) —C₁₋₆ alkyl substituted with R^(k),    -   (16) —C₁₋₆ haloalkyl substituted with R^(k),    -   (17) —C₁₋₆ alkyl-O—R^(k),    -   (18) —C₁₋₆ alkyl-O—C₁₋₆ alkyl-R^(k),    -   (19) —C₁₋₆ alkyl-S(O)_(n)—R^(k),    -   (20) —C₁₋₆ alkyl-(O)_(n)—C₁₋₆ alkyl-R^(k),    -   (21) —C₁₋₆ alkyl-N(R^(a))—R^(k),    -   (22) —C₁₋₆ alkyl-N(R^(a))—C₁₋₆ alkyl-R^(k),    -   (23) —C₁₋₆ alkyl-N(R^(a))—C₁₋₆ alkyl-OR^(k), with the proviso        that the —N(R^(a))— moiety and the —OR^(k) moiety are not both        attached to the same carbon of the —C₁₋₆ allyl-moiety,    -   (24) —C₁₋₆ alkyl-C(═O)—R^(k),    -   (25) —C₁₋₆ alkyl-C(═O)N(R^(a))—R^(k),    -   (26) —C₁₋₆ alkyl-N(R^(a))C(═O)—R^(k),    -   (27) —C₁₋₆ alkyl-C(═O)N(R^(a))—C₁₋₆ alkyl-R^(k), or    -   (28) —C₁₋₆ alkyl-N(R^(a))—C₀₋₆ alkyl-S(O)_(n)R^(k);        -   wherein R^(k) is        -   (i) aryl, which is optionally substituted with from 1 to 5            substituents each of which is independently —C₁₋₆ alkyl,            —C₁₋₆ alkyl-OH, —C₁₋₆ alkyl-O—C₁₋₆ alkyl, —C₁₋₆ alkyl-O—C₁₋₆            haloalkyl, —C₁₋₆ alkyl-N(R^(a)R^(b)), —C₁₋₆            alkyl-C(═O)N(R^(a)R^(b)), —C₁₋₆ alkyl-C(O)R^(a), —C₁₋₆            alkyl-CO₂R^(c), —C₁₋₆ alkyl-S(O)_(n)R^(c), —O—C₁₋₆ alkyl,            —C₁₋₆ haloalkyl, —O—C₁₋₆ haloalkyl, —OH, halo,            —N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(c),            —S(O)_(n)R^(c), or —SO₂N(R^(a)R^(b));        -   (ii) a 4 to 7-membered saturated or mono-unsaturated            heterocyclic ring containing at least one carbon atom and            from 1 to 4 heteroatoms independently selected from N, O and            S, wherein the heterocyclic ring is:            -   (a) optionally substituted with from 1 to 5 substituents                each of which is independently halogen, —C₁₋₆ alkyl,                —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or                oxo; and            -   (b) optionally mono-substituted with aryl or HetA;                -   wherein HetA is a 5- or 6-membered heteroaromatic                    ring containing from 1 to 4 heteroatoms                    independently selected from N, O and S, wherein the                    heteroaromatic ring is optionally fused with a                    benzene ring, and HetA is optionally substituted                    with from 1 to 4 substituents each of which is                    independently —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆                    alkyl, —O—C₁₋₆ haloalkyl, or oxo; or        -   (iii) a 5- or 6-membered heteroaromatic ring containing from            1 to 4 heteroatoms independently selected from N, O and S,            wherein the heteroaromatic ring is optionally substituted            with from optionally substituted with from 1 to 4            substituents each of which is independently —C₁₋₆ alkyl,            —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or oxo;

R⁵ is —H or —C₁₋₆ alkyl;

R⁶ is:

-   -   (1) —OH,    -   (2) —O—C₁₋₆ alkyl,    -   (3) —N(R^(u)R^(v)),    -   (4) —O—C₁₋₆ haloalkyl,    -   (5) —O—C₁₋₆ alkyl-aryl    -   (6) —O—C₁₋₆ alkyl-HetB, or    -   (7) —O—C₁₋₆ allyl-HetC,    -   wherein        -   R^(u) is —H or —C₁₋₆ alkyl;        -   R^(v) independently has the same definition as R¹;        -   HetB is a 5- or 6-membered saturated or mono-unsaturated            ring containing from 1 to 4 heteroatoms independently            selected from N, O and S, wherein the ring is optionally            substituted with from 1 to 5 substituents each of which is            independently halogen, —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆            alkyl, —O—C₁₋₆ haloalkyl, or oxo; and        -   HetC is a 5- or 6-membered heteroaromatic ring containing            from 1 to 4 heteroatoms independently selected from N, O and            S, wherein the heteroaromatic ring is optionally substituted            with from 1 to 4 substituents each of which is independently            —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆            haloalkyl, or oxo;

each R^(a) and R^(b) is independently —H or —C₁₋₆ alkyl;

each R^(c) is independently a —C₁₋₆ allyl, and

each n is independently an integer equal to 0, 1 or 2.

The present invention also includes pharmaceutical compositionscontaining a compound of the present invention and methods of preparingsuch pharmaceutical compositions. The present invention further includesmethods of treating AIDS, methods of delaying the onset of AIDS, methodsof preventing AIDS, methods of preventing infection by HIV, and methodsof treating infection by HIV.

Other embodiments, aspects and features of the present invention areeither further described in or will be apparent from the ensuingdescription, examples and appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes the8-hydroxy-1-oxo-tetrahydropyrrolopyrazines of Formula (I) above. Thesecompounds and pharmaceutically acceptable salts thereof are HIVintegrase inhibitors.

A first embodiment of the present invention is a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein R¹ is —C₁₋₄alkyl mono-substituted with aryl; wherein the aryl is optionallysubstituted with from 1 to 4 substituents each of which is independently

-   -   (1) —C₁₋₄ alkyl, optionally mono-substituted with —OH, —O—C₁₋₄        alkyl, —O—C₁₋₄ haloalkyl, —CN, —N(R^(a)R^(b)), —C(═O)N(R^(a)        ^(b)), —C(═O)R^(a), —CO₂R^(c), —S(O)_(n)R^(c),        —SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(c),        —N(R^(a))SO₂R^(c), —N(R^(a))SO₂N(R^(a)R^(b)),        —C(═O)N(R^(a)R^(b)), or —N(R^(a))C(═O)N(R^(a)R^(b)),    -   (2) —O—C₁₋₄ alkyl, optionally mono-substituted with —OH, —O—C₁₋₄        alkyl, —O—C₁₋₄ haloalkyl, —S(O)_(n)R^(c), —N(R^(a))—CO₂R^(c),        —C(═O)N(R^(a)R^(b)), —SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b),        —N(R^(a))CO₂R^(c), —N(R^(a))SO₂R^(c), —N(R^(a))SO₂N(R^(a)R^(b)),        —OC(═O)N(R^(a)R^(b)), or —N(R^(a))C(═O)N(R^(a)R^(b)),    -   (3) —C₁₋₄ haloalkyl,    -   (4) —O—C₁₋₄ haloalkyl,    -   (5) —OH,    -   (6) halo.    -   (7) —CN,    -   (8) —NO₂,    -   (9) —N(R^(a)R^(b)),    -   (10) —SR^(c),    -   (11) —S(═O)R^(c),    -   (12) —SO₂R^(c),    -   (13) —N(R^(a))SO₂R^(c),    -   (14) —SO₂N(R^(a)R^(b)),    -   (15) —N(R^(a))C(═O)R^(b), or    -   (16) —N(R^(a))CO₂R^(c);        and all other variables are as on originally defined above.

An aspect of the first embodiment is a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein

R¹ is as defined in the first embodiment;

R⁶ is:

-   -   (1) —OH,    -   (2) —O—C₁₋₆ alkyl,    -   (3) —N(R^(u)R^(v)),    -   (4) —O—C₁₋₆ haloalkyl,    -   (5) —O—C₁₋₆ alkyl-aryl    -   (6) —O—C₁₋₆ alkyl-HetB, or    -   (7) —O—C₁₋₆ allyl-HetC,    -   wherein        -   R^(u) is —H or —C₁₋₆ allyl;        -   R^(v) is —H, —C₁₋₆ alkyl, —C₃₋₆ cycloalkyl, or independently            has the same definition as R¹ above;        -   HetB is a 5- or 6-membered saturated or mono-unsaturated            ring containing from 1 to 4 heteroatoms independently            selected from N, O and S, wherein the ring is optionally            substituted with from 1 to 5 substituents each of which is            independently halogen, —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆            alkyl, —O—C₁₋₆ haloalkyl, or oxo; and        -   HetC is a 5- or 6-membered heteroaromatic ring containing            from 1 to 4 heteroatoms independently selected from N, O and            S, wherein the heteroaromatic ring is optionally substituted            with from 1 to 4 substituents each of which is independently            —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆            haloalkyl, or oxo;            and all other variables are as originally defined.

In the foregoing aspect, the reference to R^(v) having “the samedefinition as R¹ above” means that R¹ in the definition of R^(v) is asdefined in the instant embodiment, here the first embodiment, instead ofas originally defined.

A second embodiment of the present invention is a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein R¹ is—(CH₂)₁₋₄-phenyl, wherein the phenyl is optionally substituted with from1 to 3 substituents each of which is independently

-   -   (1) —C₁₋₄ alkyl, optionally mono-substituted with —OH, —O—C₁₋₄        alkyl, —O—C₁₋₄ haloalkyl, —CN, —N(R^(a)R^(b)), —C        (═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(c), S(O)_(n)R^(c), or        —SO₂N(R^(a)R^(b)),    -   (2) —O—C₁₋₄ alkyl,    -   (3) —C₁₋₄ haloalkyl,    -   (4) —O—C₁₋₄ haloalkyl,    -   (5) —OH,    -   (6) halo,    -   (7) —CN,    -   (8) —NO₂,    -   (9) —N(R^(a)R^(b)),    -   (10) —SR^(c),    -   (11) S(═O)R^(c),    -   (12) —SO₂R^(c),    -   (13) —N(R^(a))SO₂R^(c),    -   (14) —SO₂N(R^(a)R^(b)),    -   (15) —N(R^(a))C(═O)R^(b), or    -   (16) —N(R^(a))CO₂R^(c);        and all other variables are as originally defined above.

An aspect of the second embodiment is a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R¹ is as defined inthe second embodiment, R⁶ is as defined in the foregoing aspect of thefirst embodiment except that R₁ in the definition of R^(v) is as definedin the second embodiment; and all other variables are as originallydefined.

A third embodiment of the present invention is a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein R¹ is

wherein X¹ and X² are each independently

-   -   (1) —H,    -   (2) methyl,    -   (3) ethyl,    -   (4) methoxy,    -   (5) ethoxy,    -   (6) —CF₃,    -   (7) fluoro,    -   (8) bromo, or    -   (9) chloro;        and all other variables are as originally defined above.

In an aspect of the third embodiment, R¹ is 4-fluorobenzyl. Anotheraspect of the third embodiment is a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein R¹ is as defined inthe third embodiment, R⁶ is as defined in the foregoing aspect of thefirst embodiment except that R¹ in the definition of R^(v) is as definedin the third embodiment; and all other variables are as originallydefines In a feature of this aspect, R¹ is 4-fluorobenzyl.

A fourth embodiment of the present invention Is a compound of Formula(I), or a pharmaceutically acceptable salt hereof, wherein R² is is —Hor —C₁₋₄ alkyl; and all other variables are as originally defined or asdefined in any of the preceding embodiments or aspects. In an aspect ofthis embodiment, R² is —H.

A fifth embodiment of the present invention is a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein R³ is —H or—C₁₋₄ alkyl; and all other variables are as originally defined or asdefined in any of the preceding embodiments or aspects thereof. In anaspect of this embodiment, R³ is —H.

A sixth embodiment of the present invention is a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein R⁴ is:

-   -   (1) —H.    -   (2) —C₁₋₄ alkyl optionally substituted with one of —OH, —O—C₁₋₄        alkyl, —O—C₁₋₄ haloalkyl, —CN, —N(R^(a)R^(b)),        —C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(c), —S(O)_(n)R^(c),        —SO₂N(R^(a)R^(b)), —N(R^(a))—C(R^(b))═O, —N(R^(a))SO₂R^(b), or        —N(R^(a))SO₂N(R^(a)R^(b)),    -   (3) —C(═O)N(R^(a)R^(b)),    -   (4) —R^(k),    -   (5) —C₁₋₄ alkyl substituted with R^(k),    -   (6) —C₁₋₄ alkyl-O—R^(k), or    -   (7) —C₁₋₄ alkyl-O—C₁₋₄ alkyl-R^(k);        and all other variables am as originally defined or as defined        in any of the preceding embodiments or aspects thereof.

A seventh embodiment of the present invention is a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein R⁴ is:

-   -   (1) —H,    -   (2) —C₁₋₄ alkyl optionally substituted with one of —OH,        —N(R^(a)R^(b)), or —C(═O)N(R^(a)R^(b)),    -   (3) —C(═O)N(R^(a)R^(b)),    -   (4) —(CH₂)₁₋₃—R^(k),    -   (5) —(CH₂)₁₋₃—O—R^(k), or    -   (6) —CH₂)₁₋₃—O—(CH₂)₁₋₃—R^(k);        and all other variables are as originally defined or as defined        in any of the first five embodiments or aspects thereof.

An eighth embodiment of the present invention is a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein R^(k) is:

-   -   (i) phenyl, which is optionally substituted with from 1 to 3        substituents each of which is independently —C₁₋₄ alkyl, —C₁₋₄        alkyl-OH, —C₁₋₄ alkyl-O—C₁₋₄ alkyl, —C₁₋₄ alkyl-O—C₁₋₄        haloalkyl, —C₁₋₄ allyl-N(R^(a)R^(b)), —C₁₋₄        alkyl-C(═O)N(R^(a)R^(b)), —C₁₋₄ alkyl-C(═O)R^(a), —C₁₋₄        alkyl-CO₂R^(c), —C₁₋₄ alkyl-S(O)_(n)R^(c), —O—C₁₋₄ alkyl, —C₁₋₄        haloalkyl, —O—C₁₋₄ haloalkyl, —OH, halo, —N(R^(a)R^(b)),        —C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(c), S(O)_(n)R^(c), or        —SO₂N(R^(a)R^(b));    -   (ii) a 4 to 7-membered saturated heterocyclic ring containing at        least one carbon atom and a total of from 1 to 4 heteroatoms        independently selected from 1 to 4 N atoms, from O to 2 O atoms,        and from 0 to 2 S atoms, wherein the heterocyclic ring is:        -   (a) optionally substituted with from 1 to 4 substituents            each of which is independently halogen, —C₁₋₄ alkyl, —C₁₋₄            haloalkyl, —O—C₁₋₄ alkyl, O—C₁₋₄ haloalkyl, or oxo; and        -   (b) optionally mono-substituted with phenyl or HetA;            -   wherein HetA is a 5- or 6-membered heteroaromatic ring                containing a total of from 1 to 4 heteroatoms                independently selected from 1 to 4 N atoms, from 0 to 2                O atoms, and from 0 to 2 S atoms, wherein HetA is                optionally substituted with from 1 to 3 substituents                each of which is independently —C₁₋₄ alkyl, —C₁₋₄                haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, or oxo; or    -   (iii) a 5- or 6-membered heteroaromatic ring containing a total        of from 1 to 4 heteroatoms independently selected from 1 to 4 N        atoms, from 0 to 2 O atoms, and from 0 to 2 S atoms, wherein the        heteroaromatic ring is optionally substituted with from        optionally substituted with from 1 to 3 substituents each of        which is independently —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆        alkyl, O—C₁₋₆ haloalkyl, or oxo;        and all other variables are as originally defined or as defined        in any of the preceding embodiments or aspects thereof.

In an aspect of the eighth embodiment, HetA is a 5- or 6-memberedheteroaromatic ring containing 1 or 2 N atoms, wherein HetA isoptionally substituted with from 1 to 3 substituents each of which isindependently —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄haloalkyl, or oxo. In another aspect of the eighth embodiment, HetA ispyrrolyl, pyrazolyl, imidazolyl, pyridyl, or pyrazinyl; which isoptionally substituted with from 1 to 3 substituents each of which isindependently —C₁₋₄ alkyl (e.g., methyl), —C₁₋₄ haloalkyl (e.g.,trifluoromethyl), —O—C₁₋₄ alkyl (e.g., methoxy), —O—C₁₋₄ haloalkyl(e.g., —OCF₃), or oxo.

A ninth embodiment of the present invention is a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein R^(k) is:

-   -   (i) phenyl, which is optionally substituted with from 1 to 3        substituents each of which is independently —C₁₋₄ alkyl, —C₁₋₄        alkyl-OH, —C₁₋₄ alkyl-O—C₁₋₄ alkyl, —C₁₋₄ alkyl-O—C₁₋₄        haloalkyl, —C₁₋₄ alkyl-N(R^(a)R^(b)), —C₁₋₄        alkyl-C(═O)N(R^(a)R^(b)), —C₁₋₄ alkyl-C(═O)R^(a), —C₁₋₄        alkyl-CO₂R^(c), —C₁₋₄ alkyl-S(O)_(n)R^(c), —O—C₁₋₄ alkyl, —C₁₋₄        haloalkyl, —O—C₁₋₄ haloalkyl, —OH, halo, —N(R^(a)R^(b)),        —C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(c), —S(O)_(n)R^(c), or        —SO₂N(R^(a)R^(b)); or    -   (ii) a saturated heterocyclic ring selected from the group        consisting of piperidinyl, morpholinyl, thiomorpholinyl,        thiazolidinyl, isothiazolidinyl, oxazolidinyl, isooxazolidinyl,        pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl,        tetrahydrothienyl, pyrazolidinyl, hexahydropyrimidinyl,        thiazinanyl, thiazepanyl, thiadiazepanyl, dithiazepanyl,        azepanyl, diazepanyl, thiadiazinanyl, and dioxanyl; wherein the        saturated heterocyclic ring is:        -   (a) optionally substituted with from 1 to 4 substituents            each of which is independently halogen, —C₁₋₄ alkyl, —C₁₋₄            haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, or oxo; and        -   (b) optionally mono-substituted with phenyl or HetA; wherein            HetA is a heteroaromatic ring selected from the group            consisting of pyridyl, pyrrolyl, pyrazinyl, pyridinyl,            pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl,            pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl,            oxadiazolyl, oxatriazolyl, thiazolyl, isothiazolyl, and            thiadiazolyl; wherein the heteroaromatic ring is optionally            substituted with from 1 to 3 substituents each of which is            independently —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl,            —O—C₁₋₄ haloalkyl, or oxo;            and all other variables are as originally defined or as            defined in any of the first seven embodiments or aspects            thereof.

A tenth embodiment of the present invention is a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein R⁵ is —H;and all other variables are as originally defined or as defined in anyof the preceding embodiments or aspects thereof.

An eleventh embodiment of the present invention is a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein R⁶ is:

-   -   (1) —OH,    -   (2) —O—C₁₋₄ alkyl,    -   (3) —N(R^(u)R^(v)),    -   (4) —O—C₁₋₄ haloalkyl,    -   (5) —O—C₁₋₄ allyl-aryl    -   (6) —O—C₁₋₄ alkyl-HetB, or    -   (7) —O—C₁₋₄ alkyl-HetC,    -   wherein        -   R^(u) is —H or —C₁₋₄ alkyl;        -   R^(v) is —H, —C₁₋₄ alkyl, or cyclopropyl;        -   HetB is a 5- or 6-membered saturated ring containing a total            of from 1 to 4 heteroatoms independently selected from 1 to            4 N atoms, from 0 to 2 O atoms, and from 0 to 2 S atoms,            wherein the saturated zing is optionally substituted with            from 1 to 4 substituents each of which is independently            halogen, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ allyl,            —O—C₁₋₄ haloalkyl, or oxo; and        -   HetC is a 5- or 6-membered heteroaromatic ring containing a            total of from 1 to 4 heteroatoms independently selected from            1 to 4 N atoms, from 0 to 2 O atoms, and from 0 to 2 S            atoms, wherein the heteroaromatic ring is optionally            substituted with from 1 to 3 substituents each of which is            independently —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl,            —O—C₁₋₄ haloalkyl, or oxo;            and all other variables are as originally defined or as            defined in any of the first ten embodiments or aspects            thereof

A twelfth embodiment of the present invention is a compound of Formula(I), or a pharmaceutically acceptable salt thereof, wherein R⁶ is:

-   -   (1) —OH,    -   (2) —O—C₁₋₄ alkyl,    -   (3) —N(R^(u)R^(v)),    -   (4) —O—C₁₋₄ haloalkyl, or    -   (5) —O—C₁₋₄ alkyl-HetC,    -   wherein        -   R^(u) is —H or —C₁₋₄ alkyl;        -   R^(v) is —C₁₋₄ alkyl or cyclopropyl;        -   HetC is a 5- or 6-membered heteroaromatic ring containing a            total of from 1 to 4 heteroatoms independently selected from            1 to 4 N atoms, from 0 to 2 O atoms, and from 0 to 2 S            atoms, wherein the zing is attached to the remainder of the            compound via a ring carbon atom and a ring N atom is alpha            to the ring carbon attached to the remainder of the            compound; and wherein the heteroaromatic ring is optionally            substituted with from 1 to 3 substituents each of which is            independently —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl,            —O—C₁₋₄ haloalkyl, or oxo;            and all other variables are as originally defined or as            defined in any of the first ten embodiments or aspects            thereof.

A first class of tie present invention includes compounds of Formula(II), or a pharmaceutically acceptable salt thereof:

wherein:

wherein X^(1′) and X^(2′) are each independently:

-   -   (1) —H    -   (2) C₁₋₄ allyl,    -   (2) —O—C₁₋₄ alkyl,    -   (3) —C₁₋₄ haloalkyl,    -   (4) —O—C₁₋₄ haloalkyl, or    -   (5) halo; and

R^(6′) is:

-   -   (1) —OH,    -   (2) —O—C₁₋₄ alkyl, or    -   (3) —N(R^(u)R^(v));    -   wherein        -   R^(u) is —H or —C₁₋₄ alkyl; and        -   R^(v) is —C₁₋₄ alkyl or cyclopropyl.

A sub-class of the first class includes compounds of Formula (II), or apharmaceutically acceptable salt thereof, wherein:

X^(1′) and X^(2′) are each independently:

-   -   (1) —H,    -   (2) methyl,    -   (2) —OCH₃,    -   (3) —CF₃,    -   (4) —OCF₃,    -   (5) chloro,    -   (6) fluoro, or    -   (7) bromo; and

R^(6′) is:

-   -   (1) —H,    -   (2) methoxy    -   (3) ethoxy    -   (4) —N(R^(u)R^(v));    -   wherein        -   R^(u) is —H; and        -   R^(v) is methyl, ethyl, or cyclopropyl.

A second class of the present invention includes compounds of Formula(III), or a pharmaceutically acceptable salt thereof:

wherein X^(1′) and X^(2′) are each independently —H or halo; and

R^(6′) is:

-   -   (1) —OH,    -   (2) —O—C₁₋₄ allyl, or    -   (3) —N(R^(u)R^(v));    -   wherein        -   R^(u) is —H or —C₁₋₄ alkyl; and        -   R^(v) is —C₁₋₄ alkyl or cyclopropyl.

A sub-class of the second class includes compounds of Formula (III), ora pharmaceutically acceptable salt thereof, wherein:

X^(1′) and X^(2′) are each independently —H, fluoro, chloro, or bromo;and

R^(6′) is:

-   -   (1) —OH,    -   (2) methoxy    -   (3) ethoxy    -   (4) —N(R^(u)R^(v));    -   wherein        -   R^(u) is —H; and        -   R^(v) is methyl, ethyl, or cyclopropyl.

A thirteenth embodiment of the present invention is a compound ofFormula (IV), or a pharmaceutically acceptable salt thereof:

wherein

-   -   R^(u) is —H or —C₁₋₆ alkyl;    -   R^(v) is C₁₋₆ alkyl which is substituted wit 1 or 2 substituents        each of which is independently:    -   (1) C₃₋₈ cycloalkyl,    -   (2) aryl,    -   (3) a 5- or 6-membered saturated or mono-unsaturated        heterocyclic ring containing from 1 to 4 heteroatoms        independently selected from N, O and S,    -   (4) a 5- or 6-membered heteroaromatic ring containing from 1 to        4 heteroatoms independently selected from N, O and S, or    -   (5) a 9- or 10-membered fused bicyclic heterocycle containing        from 1 to 4 heteroatoms independently selected from N, O and S,        wherein at least one of the rings is aromatic;    -   wherein    -   (A) each cycloalkyl is optionally substituted with from 1 to 3        substituents, each of which is independently halo, —C₁₋₆ allyl,        or —O—C₁₋₆ alkyl;    -   (B) each aryl is optionally substituted with from 1 to 5        substituents each of which is independently        -   (1) —C₁₋₆ alkyl, optionally substituted with from 1 to 3            substituents each of which is independently —OH , —O—C₁₋₆            alkyl, —O—C₁₋₆ haloalkyl, —CN, —NO₂, —N(R^(a)R^(b)),            —C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(c), S(O)_(n)R^(c),            —SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(c),            —N(R^(a))SO₂R^(c), —N(R^(a))SO₂N(R^(a)R^(b)),            —OC(═O)N(R^(a)R^(b)), or —N(R^(a))C(═O)N(R^(a)R^(b)),        -   (2) —O—C₁₋₆ alkyl, optionally substituted with from 1 to 3            substituents each of which is independently —OH, —O—C₁₋₆            alkyl, —O—C₁₋₆ haloalkyl, —S(O)_(n)R^(c),            —C(═O)N(R^(a)R^(b)), —SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b),            —N(R^(a))CO₂R^(c), —N(R^(a))SO₂R^(c),            —N(R^(a))SO₂N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)), or            —N(R^(a))C(═O)N(R^(a)R^(b)),        -   (3) —C₁₋₆ haloalkyl,        -   (4) —O—C₁₋₆ haloalkyl,        -   (5) —OH,        -   (6) halo,        -   (7) —CN,        -   (8) —NO₂,        -   (9) —N(R^(a)R^(b)),        -   (10) —C(═O)N(R^(a)R^(b)),        -   (11) —C(═O)R^(a),        -   (12) —CO₂R^(c),        -   (13) —SR^(c),        -   (14) —S(═O)R^(c),        -   (15) —SO₂R^(c),        -   (16) —N(R^(a))SO₂R^(c),        -   (17) —SO₂N(R^(a)R^(b)),        -   (18) —N(R^(a))C(═O)R^(b), or        -   (19) —N(R^(a))CO₂R^(c);    -   (C) each saturated or mono-unsaturated heterocyclic ring is        -   (i) optionally substituted with from 1 to 5 substituents            each of which is independently halogen, —C₁₋₆ alkyl, —C₁₋₆            haloalkyl, O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or oxo; and

(ii) optionally substituted with 1 or 2 substituents each of which isindependently aryl or a 5- or 6-membered heteroaromatic ring containingfrom 1 to 4 heteroatoms independently selected from N, O and S; and

(D) each heteroaromatic ring or each fused bicyclic heterocycle is

-   -   -   (i) optionally substituted with from 1 to 7 substituents            each of which is independently halogen, —C₁₋₆ alkyl, —C₁₋₆            haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or oxo; and        -   (ii) optionally substituted with 1 or 2 substituents each of            which is independently aryl or —C₁₋₆ alkyl-aryl;

R¹ is —H or —C₁₋₆ alkyl;

and all other variables are as originally defined above or as defined inany of the previous embodiments or aspects thereof.

A fourteenth embodiment of the present invention is a compound ofFormula (IV), or a pharmaceutically acceptable salt thereof, whereinR^(v) is —C₁₋₄ alkyl mono-substituted with aryl; wherein the aryl isoptionally substituted with from 1 to 4 substituents each of which isindependently

-   -   (1) —C₁₋₄ alkyl, optionally mono-substituted with —OH, —O—C₁₋₄        alkyl, —O—C₁₋₄ haloalkyl, —CN, —N(R^(a)R^(b)), —C(═O)N(R^(a)        ^(b)), —C(═O)R^(a), —CO₂R^(c), —S(O)_(n)R^(c),        —SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(c),        —N(R^(a))SO₂R^(c), —N(R^(a))SO₂N(R^(a)R^(b)),        —C(═O)N(R^(a)R^(b)), or —N(R^(a))C(═O)N(R^(a)R^(b)),    -   (2) —O—C₁₋₄ alkyl, optionally mono-substituted with —OH, —O—C₁₋₄        alkyl, —O—C₁₋₄ haloalkyl, —S(O)_(n)R^(c), —N(R^(a))—CO₂R^(c),        —C(═O)N(R^(a)R^(b)), —SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b),        —N(R^(a))CO₂R^(c), —N(R^(a))SO₂R^(c), —N(R^(a))SO₂N(R^(a)R^(b)),        —OC(═O)N(R^(a)R^(b)), or —N(R^(a))C(═O)N(R^(a)R^(b)),    -   (3) —C₁₋₄ haloalkyl,    -   (4) —O—C₁₋₄ haloalkyl,    -   (5) —OH,    -   (6) halo.    -   (7) —CN,    -   (8) —NO₂,    -   (9) —N(R^(a)R^(b)),    -   (10) —SR^(c),    -   (11) —S(═O)R^(c),    -   (12) —SO₂R^(c),    -   (13) —N(R^(a))SO₂R^(c),    -   (14) —SO₂N(R^(a)R^(b)),    -   (15) —N(R^(a))C(═O)R^(b), or    -   (16) —N(R^(a))CO₂R^(c);        and all other variables are as first defined above for Formula        (IV).

A fifteenth embodiment of the present invention is a compound of Formula(IV), or a pharmaceutically acceptable salt thereof, wherein R^(v) is—(CH₂)₁₋₄-phenyl, wherein the phenyl is optionally substituted with from1 to 3 substituents each of which is independently

-   -   (1) —C₁₋₄ alkyl, optionally mono-substituted with —OH, —O—C₁₋₄        alkyl, —O—C₁₋₄ haloalkyl, —CN, —N(R^(a)R^(b)), —C(═O)N(R^(a)        ^(b)), —C(═O)R^(a), —CO₂R^(c), —S(O)_(n)R^(c), or        —SO₂N(R^(a)R^(b)),    -   (2) —O—C₁₋₄ alkyl,    -   (3) —C₁₋₄ haloalkyl,    -   (4) —O—C₁₋₄ haloalkyl,    -   (5) —OH,    -   (6) halo,    -   (7) —CN,    -   (8) —NO₂,    -   (9) —N(R^(a)R^(b)),    -   (10) —SR^(c),    -   (11) —S(═O)R^(c),    -   (12) —SO₂R^(c),    -   (13) —N(R^(a))SO₂R^(c),    -   (14) —SO₂N(R^(a)R^(b)),    -   (15) —N(R^(a))C(═O)R^(b), or    -   (16) —N(R^(a))CO₂R^(c);        and all other variables are -as first defined above in Formula        (IV).

A sixteenth embodiment of the present invention is a compound of Formula(IV), or a pharmaceutically acceptable salt thereof, wherein R^(v) is:

-   -   X¹ and X² are each independently    -   (1) —H,    -   (2) methyl,    -   (3) ethyl,    -   (4) methoxy,    -   (5) ethoxy,    -   (6) —CF₃,    -   (7) fluoro,    -   (8) bromo, or    -   (9) chloro;        and all other variables are as first defined above in Formula        (IV).

In an aspect of the sixteenth embodiment, R^(v) is 4-fluorobenzyl.

A seventeenth embodiment of the present invention is a compound ofFormula (IV), or a pharmaceutically acceptable salt thereof, whereinR^(u) is —H; and all other variables are as first defined in Formula(IV) or as defined in the preceding embodiments or aspects thereof.

An eighteenth embodiment of the present invention is a compound ofFormula (IV), or a pharmaceutically acceptable salt thereof, wherein R⁵is —H; and all other variables are as first defined in Formula (IV) oras defined in the preceding embodiments or aspects thereof.

A nineteenth embodiment of the present invention is a compound ofFormula (IV), or a pharmaceutically acceptable salt thereof, wherein R⁴is:

-   -   (1) —H,    -   (2) C₁₋₄ alkyl optionally substituted with one of —OH,        —N(R^(a)R^(b)), or —C(═O)N(R^(a)R^(b)),    -   (3) —C(═O)N(R^(a)R^(b)),    -   (4) —(CH₂)₁₋₃—R^(k),    -   (5) —(CH₂)₁₋₃—O—R^(k), or    -   (6) —(CH₂)₁₋₃—O—(CH₂)₁₋₃—R^(k);        and all other variables are as first defined in Formula [) or as        defined in the preceding embodiments or aspects thereof.

A twentieth embodiment of the present invention is a compound of Formula(IV), or a pharmaceutically acceptable salt thereof, wherein R^(k) isthe same as defined above in the eighth embodiment for compounds ofFormula (I); and all other variables are as originally defined inFormula (IV) or as defined in any of the preceding embodiments oraspects thereof.

In an aspect of the twentieth embodiment, HetA is a 5- or 6-memberedheteroaromatic ring containing 1 or 2 N atoms, wherein HetA isoptionally substituted with from 1 to 3 substituents each of which isindependently —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄haloalkyl, or oxo. In another aspect of the eighth embodiment, HetA ispyrrolyl, pyrazolyl, imidazolyl, pyridyl, or pyrazinyl; which isoptionally substituted with from 1 to 3 substituents each of which isindependently —C₁₋₄ alkyl (e.g., methyl), —C₁₋₄ haloalkyl (e.g.,trifluoromethyl), —O—C₁₋₄ alkyl (e.g., methoxy), —O—C₁₋₄ haloalkyl(e.g., —OCF₃), or oxo.

A twenty first embodiment of the present invention is a compound ofFormula (IV), or a pharmaceutically acceptable salt thereof, whereinR^(k) is the same as defined above in the ninth embodiment for compoundsof Formula (I); and all other variables are as originally defined inFormula (IV) or as defined in any of the preceding embodiments oraspects thereof.

A twenty-second embodiment of the present invention is a compound ofFormula (IV), or a pharmaceutically acceptable salt thereof, wherein R²is —H; and all other variables are as originally defined or as definedin the preceding embodiments or aspects thereof.

A twenty third embodiment of the present invention is a compound ofFormula (IV), or a pharmaceutically acceptable salt thereof, wherein R¹is —C₁₋₄ alkyl; and all other variables are as originally defined or asdefined in the preceding embodiments or aspects thereof. In an aspect ofthis embodiment, R¹ is methyl or ethyl.

A twenty fourth embodiment of the present invention is a compound ofFormula (IV), or a pharmaceutically acceptable salt thereof, wherein R¹is —H, methyl, or ethyl; and all other variables are as originallydefined or as defined in the preceding embodiments or aspects thereof.

A twenty-fifth embodiment of the present invention is a compoundselected from the group consisting of:

-   -   ethyl        2-benzyl-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate;    -   2-benzyl-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylic        acid;    -   ethyl        2-(4-fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate;    -   2-(4-fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylic        acid;    -   2-(4-fluorobenzyl)-8-hydroxy-N-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide;    -   2-(4-fluorobenzyl)-8-hydroxy-N-ethyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide;    -   2-(4-fluorobenzyl)-8-hydroxy-N-cycopropyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide;    -   ethyl        2-(3-chlorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate;    -   2-(3-chlorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylic        acid;    -   N-(4-fluorobenzyl)-8-hydroxy-2-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide;    -   ethyl        2-(3-fluorobenzyl-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate;    -   ethyl        2-(3,4-fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate;    -   ethyl        2-(4-chlorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate;    -   ethyl        2-(3-chloro-4-fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate;    -   ethyl        2-(3,4-dichlorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate;    -   2-(4-chlorobenzyl)-8-hydroxy-N-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide;    -   2-(3,4-difluorobenzyl)-8-hydroxy-N-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide;    -   2-(3,4-dichlorobenzyl)-8-hydroxy-N-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide;    -   and pharmaceutically acceptable salts thereof.

Other embodiments of the present invention include compounds of Formula(I) and (IV) respectively, wherein each R^(a) and R^(b) is independently—H or —C₁₋₄ alkyl; each R^(c) is independently a —C₁₋₄ alkyl; and allother variables are as originally defined or as defined in any of theforegoing embodiments or aspects thereof.

Still other embodiments of the present invention include compounds ofFormula (I) and (IV) respectively, wherein each R^(a) and R^(b) isindependently —H, methyl, or ethyl; each R^(c) is independently methylor ethyl; and all other variables are as original]y defined or asdefined in any of the foregoing embodiments or aspects thereof.

Other embodiments of the present invention include the following:

(a) A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of the invention (e.g., a compound of Formula (I)or Formula (II) or formula (III) or Formula (IV) or any of the specificcompounds set forth above) and a pharmaceutically acceptable carrier.

(b) A pharmaceutical composition which comprises the product prepared bycombining (e.g., mixing) a therapeutically effective amount of acompound of the invention and a pharmaceutically acceptable carrier

(c) The pharmaceutical composition of (a) or (b), further comprising atherapeutically effective amount of an HIV infection/AIDS treatmentagent selected from the group consisting of HIV/AIDS antiviral agents,immunomodulators, and anti-infective agents.

(d) The pharmaceutical composition of (c), wherein the HIVinfection/AIDS treatment agent is an antiviral selected from the groupconsisting of HIV protease inhibitors, non-nucleoside HIV reversetranscriptase inhibitors, and nucleoside H( reverse transcriptaseinhibitors.

(e) A combination useful for inhibiting HIV integrase, for treating orpreventing infection by HIV, or for preventing, treating or delaying theonset of AIDS, which is a therapeutically effective amount of a compoundof the invention and a therapeutically effective amount of an HIVinfection/AIDS treatment agent selected from the group consisting ofHIV/AIDS antiviral agents, immunomodulators, and anti-infective agents.

(f) The combination of (e), wherein the HIV infection/AIDS treatmentagent is an antiviral selected from the group consisting of HIV proteaseinhibitors, non-nucleoside HIV reverse transcriptase inhibitors andnucleoside HIV reverse transcriptase inhibitors.

(g) A method of inhibiting HIV integrase in a subject in need thereofwhich comprises administering to the subject a therapeutically effectiveamount of a compound of the invention.

(h) A method of preventing or treating infection by HIV in a subject inneed thereof which comprises administering to the subject atherapeutically effective amount of a compound of the invention.

(i) The method of (h), wherein the compound of the invention isadministered in combination with a therapeutically effective amount ofat least one antiviral selected-from the group consisting of HIVprotease inhibitors, non-nucleoside HIV reverse transcriptaseinhibitors, and nucleoside HIV reverse transcriptase inhibitors.

(j) A method of preventing, treating or delaying the onset of AIDS in asubject in need thereof which comprises administering to the subject atherapeutically effective amount of a compound of the invention.

(k) The method of (j), wherein the compound is administered incombination with a therapeutically effective amount of at least oneantiviral selected from the group consisting of HIV protease inhibitors,non-nucleoside HIV reverse transcriptase inhibitors, and nucleoside HIVreverse transcriptase inhibitors

(l) A method of inhibiting M integrase in a subject in need thereofwhich comprises administering to the subject the pharmaceuticalcomposition of (a), (b), (c) or (d) or the combination of (e) or (f).

(m) A method of preventing or treating infection by HIV in a subject inneed thereof which comprises administering to the subject thepharmaceutical composition of (a), (b), (c) or (d) or the combination of(e) or (f).

(n) A method of preventing, treating or delaying the onset of AIDS in asubject in need thereof which comprises administering to the subject thepharmaceutical composition of (a), (b), (c) or (d) or the combination of(e) or (f).

The present invention also includes a compound of the present invention(i) for use in, (ii) for use as a medicament for, or (iii) for use inthe preparation of a medicament for: (a) inhibiting HIV protease, (b)preventing or treating infection by HIV, or (c) preventing, treating ordelaying the onset of AIDS. In these uses, the compounds of the presentinvention can optionally be employed in combination with one or moreHIV/AIDS treatment agents selected from HIV/AIDS antiviral agents,anti-infective agents, and immunomodulators.

Additional embodiments of the invention include the pharmaceuticalcompositions, combinations and methods set forth in (a)-(n) above andthe uses set forth in the preceding paragraph, wherein the compound ofthe present invention employed therein is a compound of one of theembodiments, or an aspect or feature or subfeature thereof, describedabove,

In all of the foregoing embodiments describing compositions,combinations and methods, the compound may optionally be used in theform of a pharmaceutically acceptable salt.

As used herein, the term “C₁₋₆ alkyl” (or “C₁-C₆ alkyl”) means a linearor branched chain alkyl group having from 1 to 6 carbon atoms andincludes all of the hexyl alkyl and pentyl alkyl isomers as well as n-,iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. “C₁₋₄ alkyl”means n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.

The term “C₀” as employed in expressions such as “—C₀₋₆ alkyl-” means adirect covalent bond. For example, in the group —C₁₋₆alkyl-N(R^(a))—C₀₋₆ alkyl-S(O)_(n)R^(k), when the second alkylene groupis “C₀”, then the group is —C₁₋₆ alkyl-N(R^(a))—S(O)_(n)R^(k).

The term “—C₁₋₆ alkyl-” refers to a C₁ to C₆ linear or branched alkylgroup as just defined which is bivalent. It can alternatively bereferred to as “C₁₋₆ alkylene” or “C₁₋₆ alkanediyl”. A class ofalkylenes of particular interest with respect to the invention is—(CH₂)₁₋₆—, and sub-classes of particular interest include —(CH₂)₁₋₄—,—(CH₂)₁₋₃—, —(CH₂)₁₋₂—, and —CH₂—.

The term “C₂₋₆ alkenyl” (or “C₂-C₆ alkenyl”) means a linear or branchedchain alkenyl group having from 2 to 6 carbon atoms and includes all ofthe hexenyl and pentenyl isomers as well as 1-butenyl, 2-butenyl,3-butenyl, isobutenyl, 1-propenyl, 2-propenyl, and ethenyl (or vinyl).Similar terms such as “C₂₋₄ alkenyl” have an analogous meaning. A classof alkenyls of particular interest with respect to the invention is—CH₂═CH—(CH₂)₀₋₄H, and sub-classes of particular interest include—CH═CH—(CH₂)₁₋₂H, —CH═CH—CH₃, and —CH═CH₂. Another class of alkenyls ofparticular interest with respect to the invention is alkenyls selectedfrom —(CH₂)₂—CH═CH—(CH₂)₀₋₂H and —CH₂—CH═CH—(CH₂)₀₋₃H.

The term “C₂₋₅ alkynyl” (or “C₂-C₅ alkynyl”) means a linear or branchedchain alkynyl group having from 2 to 5 carbon atoms and includes all ofthe pentynyl isomers as well as 1-butynyl, 2-butynyl, 3-butynyl,1-propynyl, 2-propynyl, and ethynyl (or acetylenyl). Similar terms suchas “C₂₋₄ alkynyl” have an analogous meaning. A class of alkynyls ofparticular interest with respect to the invention is —C≡C—(CH₂)₁₋₄H(e.g., —C═C—CH₃). Another class of alkynyls of particular interest withrespect to the invention is alkynyls selected from —CH₂≡(CH₂)₁₋₃H and—(CH₂)₂≡(CH₂)₁₋₂H.

The term “C₃₋₈ cycloalkyl” (or “C₃-C₈ cycloalkyl”) means a cyclic ringof an alkane having three to eight total carbon atoms (i.e.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, orcyclooctyl). Similar teems such as “C₃₋₆ cycloalkyl” have an analogousmeaning.

The term “halogen” (or “halo”) refers to fluorine, chlorine, bromine andiodine (alternatively referred to as fluoro, chloro, bromo, and iodo).

The term “C₁₋₆ haloalkyl” (which may alternatively be referred to as“C₁-C₆ haloalkyl” or “halogenated C₁-C₆ alkyl”) means a C₁ to C₆ linearor branched alkyl group as defined above with one or more halogensubstituents. The term “C₁₋₄ haloalkyl” has an analogous meaning Theterm “C₁₋₆ fluoroalkyl” has an analogous meaning except that the halogensubstituents are restricted to fluoro. A class of fluoroalkyls ofparticular interest with respect to the invention is the series(CH₂)₀₋₄CF₃ (i.e., trifluorornethyl, 2,2,2-trifluoroethyl,3,3,3-trifluoro-n-propyl, etc.).

The term “oxo” means a divalent oxygen substituent; i.e., ═O. An oxosubstituent on a carbon atom in a beteroaromatic ring refers to the ketoform of the ketornol tautomer, as exemplified here for an oxopyridinylsubstituent:

Compounds of the present invention having an oxo substituent on a carbonatom of a heteroaromatic ring are understood to include compounds inwhich only the keto form is present, compounds in which only the enolform is present, and compounds in which the keto and enol forms are bothpresent.

The term “aryl” as used herein refers to an aromatic carbocyclic ring oran aromatic carbocyclic fused ring system. The fused ring systemcontains two or more carbocyclic rings in which each ring shares twoadjacent carbon atoms with at least one other ring. The aryl group maybe attached to the rest of the molecule at any carbon atom which resultsin a stable compound. A subset of aryl groups particularly suitable foruse in the present invention (e.g., in the definition of R^(k)) includesthose selected from phenyl, naphthyl, anthryl, and phenanthryl. Anotherparticularly suitable subset of aryl groups is phenyl and naphthyl.Still another particularly suitable subset of aryl groups is phenyl perse.

The term “heterocyclic ring” refers to a 4 to 8-membered, saturated orunsaturated monocyclic ring that contains one or more heteroatoms (e.g.,from 1 to 6 heteroatoms, from 1 to 5 heteroatoms, from 1 to 4heteroatoms, from 1 to 3 heteroatoms, 1 or 2 heteroatoms, or 1heteroatom) independently selected from N, O and S and a balance ofcarbon atoms (the ring typically contains at least one carbon atom); andwherein any one or more of the nitrogen and sulfur heteroatoms isoptionally oxidized, and any one or more of the nitrogen heteroatoms isoptionally quaternized. The heterocyclic Ting may be attached to therest of the molecule via any heteroatom or carbon atom in the ring,provided that attachment results in the creation of a stable structure.When the heterocyclic ring has substituents, it is understood that thesubstituents may be attached to any atom in the ring, whether aheteroatom or a carbon atom, provided that a stable chemical structureresults.

A subset of the heterocyclic rings useful in the present invention(e.g., in the definition of R^(k)) includes any 4 to 7-memberedsaturated or mono-unsaturated heterocyclic ring, wherein the ringcontains at least one carbon atom and from 1 to 4 heteroatomsindependently selected from N, O and S. A subgroup of this subsetincludes any 4- to 7-membered saturated or mono-unsaturated heterocyclicring in which the ring contains at least one carbon atom and a total offrom 1 to 4 heteroatoms independently selected from 1 to 4 N atoms, from0 to 2 O atoms, and from 0 to 2 S atoms. Representative examples ofsaturated heterocyclic rings include piperidinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl,isooxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl,tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl,hexahydropyrimidinyl, thiazinanyl

thiazepanyl, thiadiazepanyl, dithiazepanyl, azepanyl

diazepanyl, thiadiazinanyl

and dioxanyl. Representative examples of mono-unsaturated rings are thesame as the saturated rings listed in the preceding sentence except thateach zing contains a double bond.

Another subset of the heterocyclic rings useful in the present invention(e.g., in the definition of HetB) includes any 5- or 6-memberedsaturated or mono-unsaturated ring containing from 1 to 4 heteroatomsindependently selected from N, O and S. A useful subgroup of this subsetincludes any 5- or 6-membered saturated or mono-unsaturated heterocyclicring in which the ring contains at least one carbon atom and a total offrom 1 to 4 heteroatoms independently selected from 1 to 4 N atoms, from0 to 2 O atoms, and from 0 to 2 S atoms. Another useful subgroup isidentical to the preceding subgroup, except that it is limited tosaturated heterocyclic rings. Still another subgroup of this subset ofheterocyclic rings suitable for use in the present invention includesany 5- or 6-membered saturated ring containing 1 or 2 N atoms and carbonatoms. Representative examples of this subgroup include piperidinyl,pyrazolidinyl, imidazolidinyl, piperazinyl, piperidinyl, andhexahydropyrimidinyl.

Still another subset of the heterocyclic rings useful in the presentinvention are the heteroaromatic rings. The term “heteroaromatic ring”(alternatively “heteroaryl ring”) generally refers to a heterocyclicring as defined above in which the ring is an aromatic ring A usefulsubgroup of this subset (e.g., in the definition of R^(k), HetA, orHetC) includes any 5- or 6-membered monocyclic aromatic ring whichconsist of carbon atoms and from 1 to 4 heteroatoms independentlyselected from N, O and S. Representative examples of this subgroupinclude pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl,triazinyl, thienyl (or thiophenyl), thiazolyl, furanyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl,oxatriazolyl, thiazolyl, isothiazolyl, and thiadiazolyl. Another usefulsubgroup of this subset includes any 5- or 6-membered heteroaromaticring in which the ring contains a total of from 1 to 4 heteroatomsindependently selected from 1 to 4 N atoms, from 0 to 2 O atoms, andfrom 0 to 2 S atoms. Another useful subgroup includes any 5- or6-membered heteroaromatic ring containing 1 or 2 N atoms and carbonatoms

The term “fused bicyclic heterocycle” refers to any 8- to 12-memberedbicyclic ring system containing one or more heteroatoms (e.g., from 1 to6 heteroatoms, from 1 to 5 heteroatoms, from 1 to 4 heteroatoms, from 1to 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom) independentlyselected from N, O and S, in which one ring contains all of theheteroatoms or each ring contains at least one of the heteroatoms, andwherein each ring is saturated or unsaturated, and two adjacent ringatoms are shared by each of the rings in the ring system and each of thetwo shared atoms is independently a carbon atom or a heteroatom. Any oneor more of the nitrogen and sulfur heteroatoms in the ring system isoptionally oxidized, and any one or more of the nitrogen heteroatoms isoptionally quaternized. The fused bicyclic heterocycle may be attachedto the rest of the molecule via any heteroatom or carbon atom in thering, provided that attachment results in the creation of a stablestructure. When the bicyclic heterocycle has substituents, it isunderstood that the substituents may be attached to any atom in thering, whether a heteroatom or a carbon atom, provided that a stablechemical structure results.

A subset of the fused bicyclic heterocycles useful in the presentinvention (e.g., in the definition of R¹) includes any 9- or 10-memberedfused bicyclic heterocycle containing from 1 to 4 heteroatomsindependently selected from N, O and S, wherein at least one of therings is aromatic. Representative examples of bicyclic heterocycles inthis subset include benzotriazolyl, indolyl, isoindolyl, indazolyl,indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, cinnolinyl,chromanyl, isochromanyl, tetrahydroquinolinyl, quinolinyl,tetrahydroquinolinyl, isoquinolinyl, 2,3-dihydrobenzofuranyl,2,3-dihydrobenzo-1,4-dioxinyl

benzo-1,3-dioxolyl

Unless expressly stated to the contrary, an “unsaturated” ring is apartially or fully unsaturated ring.

Unless expressly stated to the contrary, all ranges cited herein areinclusive. For example, a heterocyclic Ting described as containing from“1 to 4 heteroatoms” means the ring can contain 1, 2, 3 or 4heteroatoms.

When any variable (e.g., R^(a), R^(b), or R^(c)) occurs more than onetime in any constituent or in Formula (I) or in any other formuladepicting and describing compounds of the invention, its definition oneach occurrence is independent of its definition at every otheroccurrence. Also, combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The term “substituted” (e-g., as in “each aryl is optionally substitutedwith from 1 to 5 substituents . . .”) includes mono- andpoly-substitution by a named substituent to the extent such single andmultiple substitution (including multiple substitution at the same site)is chemically allowed.

The symbol “

” in front of an open bond in the structural formula of a group marksthe point of attachment of the group to the rest of the molecule.

The compounds of the present invention may have asymmetric centers andmay occur, except when specifically noted as mixtures of stereoisomersor as individual diastereomers, or enantiomers, with all isomeric formsbeing included in the present invention.

As would be recognized by one of ordinary skill in the art, all of thecompounds of the present invention can exist as tautomers such as thefollowing:

It is to be understood for the purposes of the present invention that areference herein to a compound of Formula (I) is a reference to compoundI per se, or to any one of its tautomers per se (e.g., IA or IB), or tomixtures of two or more of the tautomers (e.g., two or more of I, IA,and IB).

The compounds of the present invention are useful in the inhibition ofHIV integrase, the prevention or treatment of infection by humanimmunodeficiency virus (HIV) and the prevention, treatment or the delayin the onset of consequent pathological conditions such as AIDS.Preventing AIDS, treating AIDS, delaying the onset of AIDS, orpreventing or treating infection by HIV is defined as including, but notlimited to, treatment of a wide range of states of HIV infection: AIDS,ARC (AIDS related complex), both symptomatic and asymptomatic, andactual or potential exposure to HIV. For example, the compounds of thisinvention are useful in treating infection by HIV after suspected pastexposure to HIV by such leans as blood transfusion, exchange of bodyfluids, bites, accidental needle stick, or exposure to patient bloodduring surgery.

The compounds of this invention are useful in the preparation andexecution of screening assays for antiviral compounds. For example, thecompounds of this invention are useful for isolating enzyme mutants,which are excellent screening tools for more powerful antiviralcompounds. Furthermore, the compounds of this invention are useful inestablishing or determining the binding site of other antivirals to HIVintegrase, e.g., by competitive inhibition. Thus the compounds of thisinvention are commercial products to be sold for these purposes.

The compounds of the present invention can be administered in the formof pharmaceutically acceptable salts. The term “pharmaceuticallyacceptable salt” refers to a salt which possesses the effectiveness ofthe parent compound and which is not biologically or otherwiseundesirable (e.g., is neither toxic nor otherwise deleterious to therecipient thereof). Suitable salts include acid addition salts whichmay, for example, be formed by mixing a solution of the compound of thepresent invention with a solution of a pharmaceutically acceptable acidsuch as hydrochloric acid, sulfuric acid, acetic acid, trifluoroaceticacid, or benzoic acid. When the compounds of the invention carry anacidic moiety, suitable pharmaceutically acceptable salts thereof caninclude alkali metal salts (e.g., sodium or potassium salts), alkalineearth metal salts (e.g., calcium or magnesium salts), and salts formedwith suitable organic ligands such as quaternary ammonium salts. Also,in the case of an acid (—COOH) or alcohol group being present,pharmaceutically acceptable esters can be employed to modify thesolubility or hydrolysis characteristics of the compound.

For the purpose of preventing or treating HIV infection or preventing,treating or delaying the onset of AIDS, the compounds of the presentinvention can be administered orally, parenterally (includingsubcutaneous injections, intravenous, intramuscular, intrasternalinjection or infusion techniques), by inhalation spray, or rectally, inthe form of a unit dosage of a pharmaceutical composition containing atherapeutically effective amount of the compound and conventionalnon-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.

The term “administration” and variants thereof (e.g., “administering” acompound) in reference to a compound of the invention mean providing thecompound to the individual in need of treatment. When a compound of theinvention is provided in combination with one or more other activeagents (e.g., antiviral agents useful for treating HIV infection orAIDS), “administration” and its variants are each understood to includeconcurrent and sequential provision of the compound and other agents.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombining the specified ingredients in the specified amounts.

By “pharmaceutically acceptable” is meant that the ingredients of thepharmaceutical composition must be compatible with each other and notdeleterious to the recipient thereof.

The term “subject” (which may be alternatively referred to herein as“patient”) as used herein refers to an animal, preferably a mammal, mostpreferably a human, who has been the object of treatment, observation orexperiment.

The term “therapeutically effective amount” as used herein means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease being treated. When the active compound (i.e., activeingredient) is administered as the salt, references to the amount ofactive ingredient are to the free acid or free base form of thecompound.

The pharmaceutical compositions can be in the form oforally-administrable suspensions or tablets or capsules, nasal sprays,sterile injectable preparations, for example, as sterile injectableaqueous or oleagenous suspensions or suppositories. These compositionscan be prepared by methods and contain excipients which are well knownin the art. Suitable methods and ingredients are described inRemington's Pharmaceutical Sciences, 18^(th) edition, edited by A. R.Gennaro, Mack Publishing Co., 1990, which is herein incorporated byreference in its entirety.

The compounds of this invention can be administered orally in a dosagerange of 0.001 to 1000 mg/kg of mammal (e.g., human) body weight per dayin a single dose or in divided doses. One preferred dosage range is 0.01to 500 mg/kg body weight per day orally in a single dose or in divideddoses. Another preferred dosage range is 0.1 to 100 mg/kg body weightper day orally in single or divided doses. For oral administration, thecompositions can be provided in the form of tablets or capsulescontaining 1.0 to 500 milligrams of the active ingredient, particularly1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. The specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

As noted above, the present invention is also directed to use of the HIVintegrase inhibitor compounds of the present invention with one or moreagents useful in the treatment of HIV infection or AIDS. For example,the compounds of this invention may be effectively administered, whetherat periods of pre-exposure and/or post-exposure, in combination witheffective amounts of one or more of the HIV/AIDS antivirals,immunomodulators, antinfectives, or vaccines useful for treating HIVinfection or AIDS. Suitable antiviral agents include those listed in thefollowing Table: Manufacturer (Tradename and/or Drug Name Location)Indication (Activity) abacavir (Glaxo Welcome HIV infection, AIDS, ARCGW 1592 (ZIAGEN ®0) (nRTI) 1592U89 abacavir + lamivudine +GlaxoSmithKline HIV infection, AIDS, ARC zidovudine (TRIZIVIR ®) (nRTIs)acemannan Carrington Labs ARC (Irving, TX) ACH 126443 Achillion Pharm.Hiv infections, AIDS, ARC (nRTI) acyclovir Burroughs Wellcome HIVinfection, AIDS, ARC, in combination with AZT AD-439 Tanox BiosystemsHIV infection, AIDS, ARC AD-519 Tanox Biosystems HIV infection, AIDS,ARC adefovir dipivoxil Gilead HIV infection, AIDS, ARC GS 840 (reversetranscriptase inhibitor) AL-721 Ethigen ARC, PGL, HIV positive, (LosAngeles, CA) AIDS alpha interferon GlaxoSmithKline Kaposi's sarcoma,HIV, in combination w/Retrovir AMD3100 AnorMed HIV infection, AIDS, ARC(CXCR4 antagonist) amprenavir GlaxoSmithKline HIV infection, AIDS, 141W94 (AGENERASE ®) ARC (PI) GW 141 VX478 (Vertex) ansamycin AdriaLaboratories ARC LM 427 (Dublin, OH) Erbamont (Stamford, CT) antibodywhich neutralizes Advanced Biotherapy AIDS, ARC pH labile alpha aberrantConcepts (Rockville, interferon MD) AR177 Aronex Pharm HIV infection,AIDS, ARC atazanavir (BMS 232632) Bristol-Myers Squibb HIV infection,AIDS, ARC (REYATAZ ™) (PI) beta-fluoro-ddA Nat'l Cancer InstituteAIDS-associated diseases BMS-232623 Bristol-Myers Squibb/ HIV infection,AIDS, (CGP-73547) Novartis ARC (PI) BMS-234475 Bristol-Myers Squibb/ HIVinfection, AIDS, (CGP-61755) Novartis ARC (PI) capravirine Pfizer HIVinfection, AIDS, (AG-1549, S-1153) ARC (nnRTI) CI-1012 Warner-LambertHIV-4 infection cidofovir Gilead Science CMV retinitis, herpes,papillomavirus curdlan sulfate AJI Pharma USA HIV infectioncytomegalovirus immune MedImmune CMV retinitis globin cytovene Syntexsight threatening CMV ganciclovir peripheral CMV retinitis delavirdinePharmacia-Upjohn HIV infection, AIDS, (RESCRIPTOR ®) ARC (nnRTI) dextranSulfate Ueno Fine Chem. Ind. AIDS, ARC, HIV Ltd. (Osaka, Japan) positiveasymptomatic ddC Hoffman-La Roche HIV infection, AIDS, ARC (zalcitabine,(HIVID ®) (nuclesodie reverse dideoxycytidine) transcriptase inhibitor)ddI Bristol-Myers Squibb HIV infection, AIDS, ARC; (didanosine,(VIDEX ®) combination with AZT/d4T dideoxyinosine) (nRTI) DPC 681 & DPC684 DuPont HIV infection, AIDS, ARC (PIs) DPC 961 & DPC 083Bristol-Myers Squibb HIV infection AIDS, ARC (from DuPont Pharma)(nnRTIs) EL10 Elan Corp, PLC HIV infection (Gainesville, GA) efavirenzBristol-Myers Squibb HIV infection, AIDS, (DMP 266) (SUSTIVA ®) ARC(non-nucleoside RT Merck (STOCRIN ®) inhibitor) famciclovir Novartisherpes zoster, herpes (FAMVIR ®) simplex emtricitabine Gilead (fromTriangle HIV infection, AIDS, ARC FTC Pharmaceuticals) (nRTI)(COVIRACIL ®) Emory University emvirine Gilead (from Triangle HIVinfection, AIDS, ARC Pharmaceuticals) (nnRTI) (COACTINON ®) enfuvirtideTrimeris & Roche HIV infection, AIDS, ARC T-20 (FUZEON ®) (fusioninhibitor) HBY097 Hoechst Marion Roussel HIV infection, AIDS, ARC(nnRTI) fosamprenavir Glaxo Smith Kline HIV infection, AIDS, ARC(prodrug of amprenavir) hypericin VIMRx Pharm. HIV infection, AIDS, ARCrecombinant human Triton Biosciences AIDS, Kaposi's sarcoma, interferonbeta (Almeda, CA) ARC interferon alfa-n3 Interferon Sciences ARC, AIDSindinavir Merck (CRIXIVAN ®) HIV infection, AIDS, ARC, asymptomatic HIVpositive, (PI) ISIS 2922 ISIS Pharmaceuticals CMV retinitisJE2147/AG1776 Agouron HIV infection, AIDS, ARC (PI) KNI-272 Nat'l CancerInstitute HIV-assoc. diseases lamivudine, 3TC GlaxoSmithKline HIVinfection, AIDS, (EPIVIR ®) ARC (nRTI) lamivudine + zidovudineGlaxoSmithKline HIV infection, AIDS, (COMBIVIR ®) ARC (nRTI) lobucavirBristol-Myers Squibb CMV infection lopinavir (ABT-378) Abbott HIVinfection, AIDS, ARC (PI) lopinavir + ritonavir Abbott (KALETRA ®) HIVinfection, AIDS, ARC (ABT-378/r) (PI) mozenavir AVID (Camden, NJ) HIVinfection, AIDS, ARC (DMP-450) (PI) nelfinavir Agouron HIV infection,AIDS, (VIRACEPT ®) ARC (PI) nevirapine Boeheringer HIV infection, AIDS,Ingleheim ARC (nnRTI) (VIRAMUNE ®) novapren Novaferon Labs, Inc. HIVinhibitor (Akron, OH) peptide T Peninsula Labs AIDS octapeptide(Belmont, CA) sequence PRO 140 Progenics HIV infection, AIDS, ARC (CCR5co-receptor inhibitor) PRO 542 Progenics HIV infection, AIDS, ARC(attachment inhibitor) trisodiuin Astra Pharm. Products, CMV retinitis,HIV infection, phosphonoformate Inc other CMV infections PNU-140690Pharmacia Upjohn HIV infection, AIDS, ARC (PI) probucol Vyrex HIVinfection, AIDS RBC-CD4 Sheffield Med. Tech HIV inCection, AIDS,(Houston TX) ARC ritonavir Abbott (NORVIR ®) HIV infection, AIDS,(ABT-538) ARC (PI) saquinavir Hoffmann-LaRoche HIV infection, AIDS,(FORTOVASE ®) ARC (PI) stavudine; d4T Bristol-Myers Squibb HIVinfection, AIDS, ARC didehydrodeoxy- (ZERIT ®) (nRTI) thymidine T-1249Trimeris HIV infection, AIDS, ARC (fusion inhibitor) TAK-779 Takeda HIVinfection, AIDS, ARC (injectable CCR5 receptor antagonist) tenofovirGilead (VIREAD ®) HIV infection, AIDS, ARC (nucleotide reversetranscriptase inhibitor) tipranavir (PNU-140690) Boebringer IngelheimHIV infection, AIDS, ARC (PI) TMC-120 & TMC-125 Tibotec HIV infections,AIDS, ARC (nnRTIs) TMC-126 Tibotec HIV infection, AIDS, ARC (PI)valaciclovir GlaxoSmithKline genital HSV & CMV infections virazoleViratek/ICN (Costa asymptomatic HIV positive, ribavirin Mesa, CA) LAS,ARC zidovudine; AZT GlaxoSimthKline HIV infection, AIDS, ARC,(RETROVIR ®) Kaposi's sarcoma in combination with other therapies (nRTI)PI = protease inhibitornnRTI = non-nucleoside reverse transcriptase inhibitornRTI = nucleoside reverse transcriptase inhibitor

A compound of the present invention can also be administered incombination with an HIV integrase inhibitor such as a compound describedin WO 99/62513,WO 99/62520, or WO 99/62897. A compound of the presentinvention can also be administered in combination with a CCR5 receptorantagonist, such as a compound described in WO 99/04794, WO 99/09984, WO99138514, WO 00/59497, WO 00159498, WO 00/59502, WO 00/59503, WO00/76511, WO 00/76512, WO 00/76513, WO 00/76514, WO 00/76792, or WO00/76793. The compounds of this invention may be effectivelyadministered, whether at periods of pre-exposure and/or post-exposure,in combination with effective amounts of one or more HIV/AIDSantivirals, immunomodulators, anti infectives, or vaccines useful fortreating HIV infection or AIDS disclosed in the Table in WO 02130930,which is herein incorporated by reference in its entirety.

It will be understood that the scope of combinations of the compounds ofthis invention with HIV/AIDS antivirals, immunomodulators,ant;-infectives or vaccines is not limited to those described orreferenced above, but includes in principle any combination with anypharmaceutical composition useful for the treatment of AIDS. TheHIV/AIDS antivirals and other agents will typically be employed in thesecombinations in their conventional dosage ranges and regimens asreported in the art, including the dosages described in the Physicians'Desk Reference, 54^(th) edition, Medical Economics Company, 2000. Thedosage ranges for a compound of the invention in these combinations arethe same as those set forth above.

Abbreviations used in the instant specification, particularly theSchemes and Examples, include the following:

-   -   AIDS=acquired immunodeficiency syndrome    -   ARC=AIDS related complex    -   Bn=benzyl    -   DMF=dimethylformamide    -   DMSO=dimethyl sulfoxide    -   ES-MS=eletron spray mass spectroscopy    -   Et=ethyl    -   HIV=human immunodeficiency virus    -   HPLC=high performance liquid chromatography    -   LC=liquid chromatography    -   LiHMDS=lithium hexamethyldisilazide    -   Me=methyl    -   MS=mass spectroscopy    -   NaHMDS=sodium hexamethyldisilazide    -   NMR nuclear magnetic resonance    -   TFA=trifluoroacetic acid    -   THF=tetrahydrofuran

The compounds of the present invention can be readily prepared accordingto the following reaction schemes and examples, or modificationsthereof, using readily available starting materials, reagents andconventional synthesis procedures. In these reactions, it is alsopossible to make use of variants which are themselves known to those ofordinary skill in this art, but are not mentioned in greater detail.Furthermore, other methods for preparing compounds of the invention willbe readily apparent to the person of ordinary skill in the art in lightof the following reaction schemes and examples. Unless otherwiseindicated, all variables are as defined above.

A general method for the preparation of compounds of the presentinvention embraced by Formula (I) is shown in Scheme 1, whereinpiperazin-2-one 1-3 is treated with dialkylalkoxymethylenemalonate 1-4and then with a deprotonating agent (e.g., Li or Nabis(trimethylsilyl)amide or Na hydride) at low temperature (e.g., fromabout 0 to about 25° C.) in an anhydrous non-protic solvent (e.g., DMFor THF) to give alkyl8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolopyrazine-7-carboxylate 1-6. Thecarboxylate 1-6 can be hydrolyzed to give the 7-carboxylic acid 1-7Carboxylate 1-6 can also be treated with amine to give the 7-carboxamide1-8.

The piperazin-2-one 1-3 reactant can be obtained by alkylation ofamine-protected piperazin-2-one 1-1 followed by deprotection to afford1-3, as depicted in Scheme 1. Compound 1-1 can be prepared using methodsdescribed in Choi et al., J. Med. Chem. 1999, 3647; Najman-Bronzewska etal., Pharmazie 1997, 198; Fryer et al., J. Org. Chem 1991, 3715,Dinsmore et al, Organic Prep. & Procedures International. 2002, 369, orroutine variations thereof. An alternative method for preparingpiperazin-2-one 1-3 is described in Bernotas et al., Tetrahedron Lett.1996, 7339; Saari et al., J. Med. Chem. 1990, 2590; Sugihara et al., J.Med. Chem. 1998, 489, Dinsmore et al, Organic Prep. & ProceduresInternational. 2002, 369, or routine variations thereof.

Some of the suitable dialkylalkoxymethylenemalonates 1-4 arecommercially available (e.g., diethylethoxymethylenemalonate ordimethylmethoxy-methylenemalonate). Others can be obtained bypreparative methods known in the art; e.g.,heterocyclylalkyloxymethylene malonates can be prepared by the methoddescribed in Boger et al., J. Org Chem 1988, 3408, or routine variationsthereof.

The protection and deprotection of the amine in the piperazin-2-one canbe accomplished using conventional amine protecting groups, such asthose described in Protective Groups in Organic Chemistry, ed, J. P. W.McOmie, Plenum Press, 1973 and in T. W. Greene & P. G. M. Wuts,Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

Scheme 2 exemplifies the same approach as set forth in Scheme 1 for thepreparation of compounds embraced by Formula (II). In Scheme 2,4-((aryl- or alkyl-oxy)carbonyl)piperazin-2-one 2-1 is alkylated withbenzyl bromide 2-2 in the presence of a base (e.g., LiHMDS, NaHMDS, orNaH) to afford 1-benzyl-4-((aryl- or alkyl-oxy)carbonyl)piperazin-2-one2-3, which can be deprotected by standard methods (e-g., treatment withhydrogen) to afford 1-benzylpiperazin-2-one 2-4. Benzylpiperazinone 2-4can then be reacted with dialkylethoxymethylenemalonate 2-5 in asuitable solvent (e.g., a hydrocarbon such as toluene) at elevatedtemperature (e.g., from about 60 to about 90° C.) to afford the2,2-dialkyloxycarbonylethenyl-substituted product 2-6. Compound 2-6 canthen be treated with a deprotonating agent (e.g., LiHMDS) in an aproticsolvent (e.g., DMF) to provide the alkyl2-benzyl-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolopyrazine-7-carboxylate2-7. Carboxylate 2-7 can be converted to the corresponding acid 2-8 byhydrolysis (e.g., with NaOH) and to the corresponding amide by treatmentwith an amine in the presence of a Lewis base (e.g., AlCl₃).

Scheme 3 illustrates a method for preparing compounds of Formula (IV).

Scheme 4 is a variation of Scheme 3 and exemplifies the preparation ofcompounds of Formula (IV) with R^(z)═H. In Scheme 4, the piperazin-2-one4-2 can be obtained by treatment of amine-protected piperazin-2-one 4-1with base (e.g., LiHMDS, NaHMDS, or NaH) in DMF, followed by addition ofmethoxymethyl chloride or similar amide protecting group. Selectivedeprotection of the amine protecting group by hydrogenolysis providespiperazin-2-one 4-3. Treatment of piperazin-2-one 4-3 withdialkylalkoxymethylenemalonate 1-4 and then with a deprotonating agentprovides 8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolopyrazine-7-carboxylate4-5. The carboxylate 4-5 can be hydrolyzed to give the 7-carboxylic acid4-6, and deprotected to provide 4-7. Carboxylate 4-5 can also be treatedwith amine to give the 7-carboxamide 4-8, and deprotected to provide4-9.

In the processes for preparing compounds of the present invention setforth in the foregoing schemes, functional groups in various moietiesand substituents may be sensitive or reactive under the reactionconditions employed and/or in the presence of the reagents employed.Such sensitivity/reactivity can interfere with the progress of thedesired reaction to reduce the yield of the desired product, or possiblyeven preclude its formation. Accordingly, it may be necessary ordesirable to protect sensitive or reactive groups on any of themolecules concerned. Protection can be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. W. McOmie, Plenum Press, 1973 and in T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis. JohnWiley & Sons, 1991. The protective groups may be removed at a convenientsubsequent stage using methods known in the art. The use of protectivegroups is illustrated in Scheme 4.

The following examples serve only to illustrate the invention and itspractice. The examples are not to be construed as limitations on thescope or spirit of the invention.

EXAMPLE 1 Ethyl2-benzyl-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate

Step 1: Benzyl 4-benzyl-3-oxopiperazine-1-carboxylate

To a cold (0° C.) solution of benzyl 3-oxopiperazine-1-carboxylate (4.7g, 20 mmol) in DMF (75 mL) under an atmosphere of nitrogen, a solutionof lithium bis(trimethylsilyl)amide in THF (24 mL, 24 mmol) was addedand stirred at the temperature for 30 min. The resultant solution wastreated with benyl bromide (2.9 mL, 24 mmol), and stirred at roomtemperature overnight. The product mixture was concentrated undervacuum, and the residue partitioned between aqueous HCl and ethylacetate. The organic extracted was washed with brine, dried overanhydrous magnesium sulfate, filtered, and concentrated under vacuum.The residue was subjected to column chromatography on silica gel elutingwith a 50-50 mixture of ethyl acetate and hexane. Collection andconcentration of appropriate fractions provided the benzylated product.

¹H NMR (400 MHz, CDCl₃) δ7.4-7.2 (m, 10H), 5.15 (s, 2H), 4.63 (s, 2H),4.25 (s, 2H), 3.66 (br t, J=5.3 Hz, 2H), 3.27 (br s, 2H).

ES MS M+1=325

Step) 2: 1-Benzylpiperazin-2-one

A mixture of benzyl 4-benzyl-3-oxopiperazine-1-carboxylate (4.7 g, 14.5mmol) and 10% Pd/C (0.47 g) in ethanol (150 mL) was stirred under anatmosphere of hydrogen (1 atm) at room temperature overnight. Theproduct mixture was filtered through a pad of Celite, and concentratedunder vacuum to provide 1-benzylpiperazin-2-one.

¹H NMR (400 MHz, CDCl₃) δ 7.4-7.2 (m, 5M, 4.61 (s, 2H), 3.60 (s, 2H),3.22 (t, J=5.2 Hz, 2H), 3.03 (t, J=5.3 Hz, 2H).

ES MS M+1=191

Step 3: Ethyl2-benzyl-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]-pyrazine-7-carboxylate

A mixture of 1-benzylpiperazin-2-one (0.29 g, 1.54 mmol) and diethylethoxymethylenemalonate (0.35 g, 1.63 mmol) in toluene was heated in asealed tube at 80° C. for 4 hours. The resultant mixture wasconcentrated under vacuum. The residue was dissolved in anhydrous DMF(10 mL), cooled to 0° C. under an atmosphere of nitrogen, and treatedwith a solution of lithium bis(trimethylsilyl)amide in THF (1 M, 2.0 mL,2.0 mmol). The reaction mixture was stirred at room temperatureovernight and concentrated under vacuum. The residue was partitionedbetween ethyl acetate and dilute aqueous HCl. The organic extract waswashed with brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated under vacuum. The residue was triturated with diethylether, and the solid precipitated was filtered to provide the titlecompound.

¹H NMR (400 MHz, CDCl₃) δ 8.39 (br s, 1H), 7.36-7.27 (m, 5H), 7.03 (s,1H), 4.67 (s, 2H), 4.31 (q, J=7.1 Hz, 2H), 4.00 (t, J=5.8 Hz, 2H), 3.51(t, J=5.8 Hz, 2H), 1.35 (t, J=7.1 Hz, 3H). ES MS M+1=315

EXAMPLE 22-Benzyl-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylicacid

A mixture of ethyl2-benzyl-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo-[1,2-a]pyrazine-7-carboxylate(0.30 g; see Example 1) and aqueous sodium hydroxide (1 M, 2 mL) inethanol (20 mL) was heated in a sealed tube at 100° C. overnight. Theproduct mixture was acidified with addition of TFA and concentratedunder vacuum. The residue was subjected to HPLC purification on C-18stationary phase eluted with water/acetonitrile/TFA mobile phase.Collection and lyophilization of appropriate fractions provided thetitle compound,

¹H NMR (400 MHz, DMSO-d₆) δ 7.37-7.25 (m, 6H), 4.62 (s, 2H), 4.09 (t,J=5.7 Hz, 2H), 3.52 (t, J=5.7 Hz, 2H).

ES MS M+1=287

EXAMPLE 3 Ethyl2-(4-fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-]pyrazine-7-carboxylate

The title compound was prepared using a procedure similar to thatdescribed in Example 1, except that benzyl bromide (Step 1) wassubstituted with 4-fluorobenzyl bromide.

¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (s, 1H), 7.40 (dd, J=8.3, 5.8 Hz, 2H),7.36 (s, 1H), 7.17 (t, J=8-3 Hz, 2H), 4.59 (s, 2H), 4.18 (q, J=7.1 Hz,2H), 4.01 (t, J=5.3 Hz, 2H), 3.53 (t, J=5.3 Hz, 2H), 1.24 (t, J=7.1 Hz,3H).

ES MS M+1=333

EXAMPLE 42-(4-Fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylicacid

The title compound was prepared using a procedure similar to thatdescribed in Example 2, except that ethyl2-benzyl-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylatewas substituted wit ethyl2-(4-fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate.

¹H NMR (400 MHz, DMSO-d₆) δ 8.6 (br s, 1H), 7.40 (dd, J=8.3, 5.8 Hz,2H), 7.31 (s, 1H), 7.36 (s, 1H), 7.17 (t, J=8.3 Hz, 2H), 4.59 (s, 2H),4.09 (t, J=5.5 Hz, 2H), 3.52 (t, J=5.5 Hz, 2H).

ES MS M+1=305

EXAMPLE 52-(4-Fluorobenzyl)-8-hydroxy-N-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2a]pyrazine-7-carboxamide

Anhydrous methylamine gas was bubbled through a mixture of ethyl2-(4-fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate(200 mg) and anhydrous aluminum chloride (200 mg) in anhydrouschloroform at 0° C. for 5 minutes. The resistant mixture was heated in aseal tube at 70° C. overnight and concentrated under vacuum. The residuewas dissolved in DMSO and acidified with TFA. The solution was subjectedto HPLC purification on C-18 stationary phase eluted withwater/acetonitrile/ TFA mobile phase. Collection and lyophilization ofappropriate fractions provided the title compound

¹H NMR (400 Mz, DMSO-d₆) δ 7.71 (br q, J=4.6, 1H), 7.35 (dd, J=8.6, 5.7Hz, 2H), 7.24 (s, 1H), 7.17 (t, J=8.6 Hz, 2H), 4.59 (s, 2M), 4.07 (t,J=5.3 Hz, 2H), 3.50 (t, J=5.2 Hz, 2H), 2.74 (s, 3H).

ES MS M+1=318

EXAMPLE 62-(2-Fluorobenzyl)-8-hydroxy-N-ethyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide

The title compound was prepared using a procedure similar to thatdescribed in Example 5, except that methylamine was substituted withethylamine.

¹H NMR (400 Mz, DMSO-d₆) δ 7.76 (br t, J=53, 1H), 7.35 (dd, J=8.7, 5.6Hz, 2H), 7.27 (s 1H), 7.17 (t, J=8.8 Hz, 2H), 4.59 (s, 2H), 4.07 (t,J=5.9 Hz, 2H), 3.50 (t, J=5.9 Hz, 2H), 3.25 (m, 2H), 1.09 (t, J=7.1 Hz,3H).

ES MS M+1=332

EXAMPLE 72-(4Fluorobenzyl)-8-hydroxy-N-cyclopropyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2a]pyrazine-7-carboxamide

The title compound was prepared using a procedure similar to thatdescribed in Example 5, except that methylamine was substituted withcyclopropyl amine.

¹H NMR (400 Mz, DMSO-d₆) δ 7.76 (br d, J=3.2, 1H), 7.35 (dd, J=8.2, 5.6Hz, 2H), 7.26 (s 1H), 7.17 (t, J=8.9 Hz, 2H), 4.59 (s, 2H), 4.06 (t,J=5.9 Hz, 2H), 3.50 (t, J=5.9 Hz, 2H), 2.75 (m, 1H), 0.69 (m, 2H), 0.49(m, 2H).

ES MS M+1=344

EXAMPLE 8 Ethyl2(3-chlorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate

Step1; 1-(3-chlorobenzyl)piperazin-2-one

To a cold (0° C.) solution of 4-[(tert-butoxy)carbonyl]-piperazin-2-one(4.0 g, 20 mmol) in DMF (175 mL) under an atmosphere of nitrogen, asolution of lithium bis(trimethylsilyl)amide in THF (22 mL, 22 mmol) wasadded and stilled at the temperature for 30 min. The resultant solutionwas treated with 3-chlorobenzyl bromide (2.6 mL, 20 mmol), and stirredat room temperature overnight. The product mixture was concentratedunder vacuum, and the residue partitioned between 0.1 M aqueous HCl andethyl acetate. The organic extracted was washed with brine, dried overanhydrous magnesium sulfate, filtered, and concentrated under vacuum.The residue was subjected to column chromatography on silica gel elutingwith a 50-50 mixture of ethyl acetate and hexane Collection andconcentration of appropriate fractions provided the benzylated productThe product was dissolved in ethyl acetate (150 mL) and cooled to 0° C.A steady steam of anhydrous HCl gas was bubbled through for 10 minutes.The resultant mixture was capped and stirred at the same temperature for1 hour. The product mixture was concentrated under vacuum. The residuewas treated with chloroform saturated with ammonia, and the resultantsuspension was filtered through a pad of Celite. The filtrate wasconcentrated under vacuum provided the title amine. Residual ammonia wasremoved by concentrating the residue three time with toluene undervacuum

ES MS M+1=225

Step 2: Ethyl2-(3-chlorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]-pyrazine-7-carboxylate

A mixture of 1-(3-chlorobenzyl)piperazin-2-one (3.97 g, 17.67 mmol) anddiethyl ethoxymethylenemalonate (4.01 g, 18.55 mmol) in toluene (60 mL)was heated in a sealed tube at 80° C. overnight. The resultant mixturewas concentrated under vacuum. The residue was dissolved in anhydrousDMF (200 mL), cooled to 0° C. under an atmosphere of nitrogen, andtreated with a solution of lithium bis(trimethylsilyl)amide in THF (1 M,21.2 mL, 21.2 mmol). The reaction mixture was stirred at roomtemperature overnight and concentrated under vacuum. The residue waspartitioned between ethyl acetate and dilute aqueous HCl. The organicextract was washed with brine, dried over anhydrous magnesium sulfate,filtered, and concentrated under vacuum. The residue was triturated withdiethyl ether, and the solid precipitated was filtered to provide thetitle compound.

¹H NMR (400 Mz, DMSO-d₆) δ 8.60 (s, 1H), 7.41-7.28 (m, 5H), 4.62 (s,2H), 4.19 (q, J=7.2 Hz, 2H), 4.11 (t, J=5.9 Hz, 2H), 3.57 (t, J=5.9 Hz,2H), 1.25 (t, J=7.2 Hz, 3H).

ES MS M+1=349

EXAMPLE 92-(3-Chlorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylicacid

The title compound was prepared using a procedure similar to thatdescribed in Example 2, except that ethyl2-benzyl-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo-[1,2-a]pyrazine-7-carboxylatewas substituted with ethyl2-(3-chlorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate.

¹H NMR (400 Mz, DMSO-d₆) δ 12.33 (br s, 1H), 8.69 (br s, 1H), 7.41-7.27(m, 5H), 4.61 (s, 2H), 4.10 (t, J=5.3 Hz, 2H), 3.55 (t, J=5.3 Hz, 2H).

ES MS M+1=322

EXAMPLE 10N-(4-Fluorobenzyl)-8-hydroxy-2-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide

Step 1: 1-Methylpiperazin-2-one

The title compound was prepared using a procedure similar to thatdescribed in Example 1 (Step 1 & 2), except that benzyl bromide (Step 1)was substituted with methyl iodide.

ES MS M+1=115

Step 2: Ethyl8-hydroxy-2-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate

The title compound was prepared using a procedure similar to thatdescribed in Example 1 (Step 3), except that 1-benzylpiperazin-2-one wassubstituted with 1-methylpiperazin-2one.

ES MS M+1=238

Step 3:N-(4-Fluorobenzyl)-8-hydroxy-2-methyl-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazine-7-carboxamide

The tile compound was prepared using a procedure similar to thatdescribed in Example 5, except that methylamine was substituted with4-fluorobenzyl-amine.

ES MS M+1=318

EXAMPLE 11 Ethyl2-(3-fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate

The title compound was prepared using a procedure similar to thatdescribed in Example 1, except that benzyl bromide (Step 1) wassubstituted with 3-fluorobenzyl bromide.

¹H NMR (400 Mz, DMSO-d₆) δ 7.36 (dd, J=8, 8 Hz, 1H), 7.2-6.8 (m, 5 H),4.57 (s, 2H), 4.05 (q, J=7.1 Hz, 2H), 4.01 (t, J=5.3 Hz, 2H), 3.53 (t,J=5.3 Hz, 2H), 1.18 (t, J=7.1 Hz, 3H).

ES MS M+1=333

EXAMPLE 12 Ethyl2(3,4-fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate

The title compound was prepared using a procedure similar to thatdescribed in Example 1, except that benzyl bromide (Step 1) wassubstituted with 3,4-difluorobenzyl bromide.

¹H NMR (400 Mz, DMSO-d₆) δ 7.43-6.82 (m, 51), 4.58 (s, 2H), 4.18 (q,J=7.0 Hz, 2H), 4.02 (t, J=5.3 Hz, 2H), 3.52 (t, J=5.3 Hz, 2H), 1.23 (t,J=7.0 Hz, 3H).

ES MS M+1=351

EXAMPLE 13 Ethyl2-(4-chlorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate

Step 1: tert-Butyl 4-(chlorobenzyl)-3-oxopiperazine-1-carboxylate

To a cold (0° C.) solution of tert-butyl 3-oxopiperazine-1-carboxylate(2.0 g, 9.9 mmol) in DMF (100 mL) under an atmosphere of nitrogen, asolution of lithium bis(trimethylsilyl)amide in THF (10.9 mL, 10.9 mmol)was added and stirred at the temperature for 30 min The resultantsolution was treated with 4-chlorobenzyl bromide (2.1, 10.5 mmol), andstirred at room temperature overtight. The product mixture wasconcentrated under vacuum, and the residue partitioned between aqueousHCl and ethyl acetate. The organic extracted was washed with brine,dried over anhydrous magnesium sulfate, filtered, and concentrated undervacuum. The residue was subjected to column chromatography on silica geleluting with a mixture of ethyl acetate and dichloro-methane (0 to 50%gradient). Collection and concentration of appropriate fractionsprovided the benzylated product.

¹H NMR (400 Mz, CDCl₃) δ 7.31 (br d, J=8.5 H, 2H), 7.20 (br d, J=8.5 H,2H), 4.58 (s, 2H), 4.15 (s, 2H), 3.59 (br t, J=5.3 Hz, 2H), 3.25 (br t,2H).

ES MS M+1=325

Step 2: 1-(4Chlorobenzyl)-piperazin-2-one

A cold (0° C.) solution of tert-Butyl4-(4-chlorobenzyl)-3-oxopiperazine-1-carboxylate (3.2 g, 9.9 mmol) inethyl acetate (100 mL) was saturated with HCl gas. The resultant mixturewas stirred at 0° C. for 1 h. The product mixture was concentrated undervacuum. The residue was treated with dichloromethane saturated withammonia gas. The resultant chalky mixture was filtered, and the filtrateconcentrated under vacuum. The residue was diluted with benzene andconcentrated under vacuum to provide 1-(4-chlorobenzyl)-piperazin-2-one.

ES MS M+1=225

Step 3: Ethyl2-(4-chlorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate

A mixture of 1-(4-chlorobenzyl)-piperazin-2-one (1.94 g, 8.63 mmol) anddiethyl ethoxymethylenemalonate (1.87 g, 8.63 mmol) in toluene (40 mL)was heated in a sealed tube at 80° C. overnight The resultant mixturewas concentrated under vacuum. The residue was dissolved in anhydrousDMF (50 mL), cooled to 0° C. under an atmosphere of nitrogen, andtreated with a solution of lithium bis(trimethylsilyl)amide in THF (1 M,12 mL, 12 mmol). The reaction mixture was stirred at room temperatureovernight and concentrated under vacuum. The residue was partitionedbetween ethyl acetate and dilute aqueous HCl. The organic extract waswashed with brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated under vacuum The residue was subjected to HPLC purificationon C-18 stationary phase eluted with water/acetonitrile/TFA mobilephase. Collection and lyophilization of appropriate fractions providedthe title compound.

¹H NMR (400 Mz, DMSO-d₆) δ 7.37 (d, J=8.3, 2H), 7.30 (d, J=8.3, 2H),7.09 (s, 1H), 4.55 (s, 2H), 4.05 (q, J=7.1 Hz, 2H), 4.01 (br t, 2H),3.53 (br t, 2H), 1.19 (t, J=7.1 Hz, 2H).

ES MS M+1=349

EXAMPLE 14 Ethyl2-(3-chloro-4-fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate

The title compound was prepared using a procedure similar to thatdescribed in Example 13, except that 4-chlorobenzyl bromide (Step 1) wassubstituted with 3-chloro-4-fluorobenzyl bromide.

¹H NMR (400 Mz, DMSO-d₆) δ 8.58 (s, 1H), 7.4-7.3 (m, 4 H), 4.59 (s, 2H),4.18 (q, J=7.1 Hz, 2H), 4.11 (t, J=5.3 Hz, 2H), 3.56 (t, J=5.3 Hz, 2H),1.24 (t, J=7.1 Hz, 2H),

ES MS M+1=367

EXAMPLE 15 Ethyl2-(3,4-dichlorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate

The title compound was prepared using a procedure similar to thatdescribed in Example 13, except that 4-chlorobenzyl bromide (Step 1) wassubstituted with 3,4-dichlorobenzyl bromide.

¹H NMR (400 Mz, DMSO-d₆) δ 8.59 (s, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.58(d, J=1.8 Hz, 1H), 7.37 (s, 1H), 7.31 (dd, J=8.4, 1.8 Hz, 1H), 4.60 (s,2H), 4.18 (q, J=7.0 Hz, 2H), 4.11 (t, J=5.8 Hz, 2H), 3.57 (t, J=5.8 Hz,2H), 1.24 (t, J=7.0 Hz, 3H).

ES MS M+1=383

EXAMPLE 162-(4-Chlorobenzyl)-8-hydroxy-N-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide

The title compound was prepared using a procedure similar to thatdescribed in Example 5, except that ethyl2-(4-fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylatewas substituted with ethyl2-(4-chlorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate(Example 13).

¹H NMR (400 Mz, CDCl₃) δ 7.33 (d, J=8.2, 1H), 7.27-7.21 (m), 7.18 (s,1H), 4.65 (s, 2H), 4.03 (t, J=6.3 Hz, 2H), 3.53 (t, J=6.3 Hz, 2H), 2.99(d, J=4.8 Hz, 3H).

ES MS M+1=334

EXAMPLE 172-(3,4-Difluorobenzyl)-8-hydroxy-N-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide

The title compound was prepared using a procedure similar to thatdescribed in Example 5, except that ethyl2-(4-fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylatewas substituted with ethyl2-(3,4-difluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate(Example 12).

¹H NMR (400 Mz, CDCl₃) δ 7.34-7.05 (m), 6.74 (br s, 1H), 4.64 (s, 2H),4.05 (t, J=5.7 Hz, 2H), 3.54 (t, J=57 Hz, 2H), 2.99 (d, J=4.6 Hz, 3H).

ES MS M+1=336

EXAMPLE 182-(3,4-Dichlorobenzyl)-8-hydroxy-N-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxamide

The title compound was prepared using a procedure similar to thatdescribed in Example 5, except that ethyl2-(4-fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylatewas substituted with ethyl2-(3,4-dichlorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate(Example 15).

¹H NMR (400 Mz, CDCl₃) δ 7.43 (d, J=8.4 Hz, 1H), 7.40 (d, J=1.8 Hz, 1H),7.19 (s, 1H), 7.16 (dd, J=8.4, 1.8 Hz, 1H), 4.64 (s, 2H), 4.05 (t, J=5.7Hz, 2H), 3.54 (t, J=5.7 Hz, 2H), 2.99 (d, J=4.6 Hz, 3H).

ES MS M+1=368

EXAMPLE 19

Oral Compositions

As a specific embodiment of an oral composition of a compound of thisinvention, 50 mg of compound of Example 1 is formulated with sufficientfinely divided lactose to provide a total amount of 580 to 590 mg tofill a size 0 hard gelatin capsule. Encapsulated oral compositionscontaining any one of the compounds of Examples 2-18 can be similarlyprepared.

EXAMPLE 20

HIV Integrase Assay: Strand Transfer Catalyzed by Recombinant Integrase

Assays for the strand transfer activity of integrase were conducted inaccordance with WO 02/30930 for recombinant integrase. Representativecompounds of the present invention exhibit inhibition of strand transferactivity in this assay. For example, the compounds prepared in Examples1-18 were tested in the integrase assay and all were found to haveIC₅₀'s less than 1.5 micromolar In particular, the compounds prepared inExamples 1-10 were all found to have IC₅₀'s less than 0.7 micromolar inthe integrase assay.

Further description on conducting the assay using preassembled complexesis found in Wolfe, A. L. et al., J. Virol. 1996, 70: 1424-1432, Hazudaet al., J. Virol. 1997, 71: 7005-7011; Hazuda et al., Drug Design andDiscovery 1997, 15: 17-24; and Hazuda et al., Science 2000, 287:646-650.

EXAMPLE 21

Assay for Inhibition of HIV Replication

Assays for the inhibition of acute HIV infection of T-lymphoid cellswere conducted in accordance with Vacca, J. P. et al., Proc. Natl. Acad.Sci. USA 1994, 91: 4096. Representative compounds of the presentinvention exhibit inhibition of HIV replication in this assay. Forexample, the compounds prepared in Examples 1, 3, 5-8, 10, 16 and 17were found to have IC₉₅'s at or less than 20 micromolar in the presentassay.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, thepractice of the invention encompasses all of the usual variations,adaptations and/or modifications that come within the scope of thefollowing claim.

1. A compound of Formula (I), or a pharmaceutically acceptable saltthereof:

wherein R¹ is —H, —C₁₋₆ alkyl, —C₃₋₆ cycloalkyl, or —C₁₋₆ alkyl which issubstituted with 1 or 2 substituents each of which is independently: (1)C₃₋₈ cycloalkyl, (2) aryl, (3) a 5- or 6-membered saturated ormono-unsaturated heterocyclic ring containing from 1 to 4 heteroatomsindependently selected from N, O and S, (4) a 5- or 6-memberedheteroaromatic ring containing from 1 to 4 heteroatoms independentlyselected from N, O and S, or (5) a 9- or 10-membered fused bicyclicheterocycle containing from 1 to 4 heteroatoms independently selectedfrom N, O and S, wherein at least one of the rings is aromatic; wherein(A) each cycloalkyl is optionally substituted with from 1 to 3substituents, each of which is independently halo, —C₁₋₆ alkyl, or—O—C₁₋₆ alkyl; (B) each aryl is optionally substituted with from 1 to 5substituents each of which is independently (1) —C₁₋₆ alkyl, optionallysubstituted with from 1 to 3 substituents each of which is independently—OH, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —CN, —NO₂, —N(R^(a)R^(b)),—C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(c), —S(O)_(n)R^(c),—SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(c),—N(R^(a))SO₂R^(c), —N(R^(a))SO₂N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)), or—N(R^(a))C(═O)N(R^(a)R^(b)), (2) —O—C₁₋₆ alkyl, optionally substitutedwith from 1 to 3 substituents each of which is independently —OH,—O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —S(O)_(n)R^(c), —C(═O)N(R^(a)R^(b)),—SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(c),—N(R^(a))SO₂R^(c), —N(R^(a))SO₂N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)), or—N(R^(a))C(═O)N(R^(a)R^(b)), (3) —C₁₋₆ haloalkyl, (4) —O—C₁₋₆ haloalkyl,(5) —OH, (6) halo, (7) —CN, (8) —NO₂, (9) —N(R^(a)R^(b)), (10)—C(═O)N(R^(a)R^(b)), (11) —C(═O)R^(a), (12) —CO₂R^(c), (13) —SR^(c),(14) —S(═O)R^(c), (15) —SO₂R^(c), (16) —N(R^(a))SO₂R^(c), (17)—SO₂N(R^(a)R^(b)), (18) —N(R^(a))C(═O)R^(b), or (19) —N(R^(a))CO₂R^(c);(C) each saturated or mono-unsaturated heterocyclic ring is (i)optionally substituted with from 1 to 5 substituents each of which isindependently halogen, —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl,—O—C₁₋₆ haloalkyl, or oxo; and (ii) optionally substituted with 1 or 2substituents each of which is independently aryl or a 5- or 6-memberedheteroaromatic ring containing from 1 to 4 heteroatoms independentlyselected from N, O and S; and (D) each heteroaromatic ring or each fusedbicyclic heterocycle is (i) optionally substituted with from 1 to 7substituents each of which is independently halogen, —C₁₋₆ alkyl, —C₁₋₆haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or oxo; and (ii) optionallysubstituted with 1 or 2 substituents each of which is independently arylor —C₁₋₆ alkyl-aryl; R² is —H or —C₁₋₆ alkyl; R³ is —H, —C₁₋₆ alkyl,—C₁₋₆ haloalkyl, or —C₁₋₆ alkyl substituted with one of —OH, —O—C₁₋₆alkyl, —O—C₁₋₆ haloalkyl, —CN, —NO₂, —N(R^(a)R^(b)), —C(═O)N(R^(a)),—C(═O)R^(a), —CO₂R^(c), —S(O)_(n)R^(c), —SO₂N(R^(a)R^(b)),—N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(c), —N(R^(a))SO₂R^(c),—N(R^(a))SO₂N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)), or—N(R^(a))C(═O)N(R^(a)R^(b)); R⁴ is: (1) —H, (2) —C₁₋₆ alkyl optionallysubstituted with one of —OH, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —CN,—NO₂, —N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(c),—S(O)_(n)R^(c), —SO₂N(R^(a)R^(b)), —N(R^(a))—C(R^(b))═O,—N(R^(a))SO₂R^(c), —N(R^(a))SO₂N(R^(a)R^(b)), —OC(═O)N(R^(a) ^(b)),—N(R^(a))C(═O)N(R^(a)R^(b)), —O—C₁₋₆ alkyl-C(═O)N(R^(a)R^(b)), —S—C₁₋₆alkyl-C(═O)N(R^(a)R^(b)), —N(R^(a))—C₁₋₆ alkyl-C(═O)N(R^(a)R^(b)), or—N(SO₂R^(c))—C₁₋₆ alkyl-C(═O)N(R^(a)R^(b)), (3) —C₁₋₆ haloalkyl, (4)—C(═O)R^(a), (5) —CO₂R^(c), (6) —C(═O)N(R^(a)R^(b)), (7)—SO₂N(R^(a)R^(b)), (8) —C₂₋₆ alkenyl, (9) —C₂₋₆ alkenyl-C(═O)—N(R^(a))₂,(10) —C₂₋₅ alkynyl, (11) —C₂₋₅ alkynyl-CH₂N(R^(a))₂, (12) —C₂₋₅alkynyl-CH₂OR^(a), (13) —C₂₋₅ alkynyl-CH₂S(O)_(n)R^(c), or (14) —R^(k),(15) —C₁₋₆ alkyl substituted with R^(k), (16) —C₁₋₆ haloalkylsubstituted with R^(k), (17) —C₁₋₆ alkyl-O—R^(k), (18) —C₁₋₆alkyl-O—C₁₋₆ alkyl-R^(k), (19) —C₁₋₆ alkyl-S(O)_(n)—R^(k), (20) —C₁₋₆alkyl-(O)_(n)—C₁₋₆ alkyl-R^(k), (21) —C₁₋₆ alkyl-N(R^(a))—R^(k), (22)—C₁₋₆ alkyl-N(R^(a))—C₁₋₆ alkyl-R^(k), (23) —C₁₋₆ alkyl-N(R^(a))—C₁₋₆alkyl-OR^(k), with the proviso that the —N(R^(a))— moiety and the—OR^(k) moiety are not both attached to the same carbon of the —C₁₋₆allyl-moiety, (24) —C₁₋₆ alkyl-C(═O)—R^(k), (25) —C₁₋₆alkyl-C(═O)N(R^(a))—R^(k), (26) —C₁₋₆ alkyl-N(R^(a))C(═O)—R^(k), (27)—C₁₋₆ alkyl-C(═O)N(R^(a))—C₁₋₆ alkyl-R^(k), or (28) —C₁₋₆alkyl-N(R^(a))—C₀₋₆ alkly-S(O)_(n)R^(k); wherein R^(k) is (i) aryl,which is optionally substituted with from 1 to 5 substituents each ofwhich is independently —C₁₋₆ alkyl, —C₁₋₆ alkyl-OH, —C₁₋₆ alkyl-O—C₁₋₆alkyl, —C₁₋₆ alkyl-O—C₁₋₆ haloalkyl, —C₁₋₆ alkyl-N(R^(a)R^(b)), —C₁₋₆alkyl-C(═O)N(R^(a)R^(b)), —C₁₋₆ alkyl-C(O)R^(a), —C₁₋₆ alkyl-CO₂R^(c),—C₁₋₆ alkyl-S(O)_(n)R^(c), —O—C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆haloalkyl, —OH, halo, —N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —C(═O)R^(a),—CO₂R^(c), —S(O)_(n)R^(c), or —SO₂N(R^(a)R^(b)); (ii) a 4 to 7-memberedsaturated or mono-unsaturated heterocyclic ring containing at least onecarbon atom and from 1 to 4 heteroatoms independently selected from N, Oand S, wherein the heterocyclic ring is: (a) optionally substituted withfrom 1 to 5 substituents each of which is independently halogen, —C₁₋₆alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or oxo; and(b) optionally mono-substituted with aryl or HetA;  wherein HetA is a 5-or 6-membered heteroaromatic ring containing from 1 to 4 heteroatomsindependently selected from N, O and S, wherein the heteroaromatic ringis optionally fused with a benzene ring, and HetA is optionallysubstituted with from 1 to 4 substituents each of which is independently—C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or oxo;or (iii) a 5- or 6-membered heteroaromatic ring containing from 1 to 4heteroatoms independently selected from N, O and S, wherein theheteroaromatic ring is optionally substituted with from optionallysubstituted with from 1 to 4 substituents each of which is independently—C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or oxo;R⁵ is —H or —C₁₋₆ alkyl; R⁶ is: (1) —OH, (2) —O—C₁₋₆ alkyl, (3)—N(R^(u)R^(v)), (4) —O—C₁₋₆ haloalkyl, (5) —O—C₁₋₆ alkyl-aryl (6)—O—C₁₋₆ alkyl-HetB, or (7) —O—C₁₋₆ allyl-HetC, wherein R^(u) is —H or—C₁₋₆ alkyl; R^(v) independently has the same definition as R¹; HetB isa 5- or 6-membered saturated or mono-unsaturated ring containing from 1to 4 heteroatoms independently selected from N, O and S, wherein thering is optionally substituted with from 1 to 5 substituents each ofwhich is independently halogen, —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆alkyl, —O—C₁₋₆ haloalkyl, or oxo; and HetC is a 5- or 6-memberedheteroaromatic ring containing from 1 to 4 heteroatoms independentlyselected from N, O and S, wherein the heteroaromatic ring is optionallysubstituted with from 1 to 4 substituents each of which is independently—C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or oxo;each R^(a) and R^(b) is independently —H or —C₁₋₆ alkyl; each R^(c) isindependently a —C₁₋₆ alkyl; and each n is independently an integerequal to 0, 1 or
 2. 2. The compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein: R¹ is —C₁₋₄ alkylmono-substituted with aryl; wherein the aryl is optionally substitutedwith from 1 to 4 substituents each of which is independently (1) —C₁₋₄alkyl, optionally mono-substituted with —OH, —O—C₁₋₄ alkyl, —O—C₁₋₄haloalkyl, —CN, —N(R^(a)R^(b)), —C(═O)N(R^(a) ^(b)), —C(═O)R^(a),—CO₂R^(c), —S(O)_(n)R^(c), —SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b),—N(R^(a))CO₂R^(c), —N(R^(a))SO₂R^(c), —N(R^(a))SO₂N(R^(a)R^(b)),—OC(═O)N(R^(a)R^(b)), or —N(R^(a))C(═O)N(R^(a)R^(b)), (2) —O—C₁₋₄ alkyl,optionally mono-substituted with —OH, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl,—S(O)_(n)R^(c), —N(R^(a))—CO₂R^(c), —C(═O)N(R^(a)R^(b)),—SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(c),—N(R^(a))SO₂R^(c), —N(R^(a))SO₂N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)), or—N(R^(a))C(═O)N(R^(a)R^(b)), (3) —C₁₋₄ haloalkyl, (4) —O—C₁₋₄ haloalkyl,(5) —OH, (6) halo. (7) —CN, (8) —NO₂, (9) —N(R^(a)R^(b)), (10) —SR^(c),(11) —S(═O)R^(c), (12) —SO₂R^(c), (13) —N(R^(a))SO₂R^(c), (14)—SO₂N(R^(a)R^(b)), (15) —N(R^(a))C(═O)R^(b), or (16) —N(R^(a))CO₂R^(c);R⁶ is: (1) —OH, (2) —O—C₁₋₆ alkyl, (3) —N(R^(u)R^(v)), (4) —O—C₁₋₆haloalkyl, (5) —O—C₁₋₆ alkyl-aryl (6) —O—C₁₋₆ alkyl-HetB, or (7) —O—C₁₋₆alkyl-HetC, wherein R^(u) is —H or —C₁₋₆ alkyl; R^(v) is —H, —C₁₋₆alkyl, —C₃₋₆ cycloalkyl, or independently has the same definition as R¹above; HetB is a 5- or 6-membered saturated or mono-unsaturated ringcontaining from 1 to 4 heteroatoms independently selected from N, O andS, wherein the ring is optionally substituted with from 1 to 5substituents each of which is independently halogen, —C₁₋₆ alkyl, —C₁₋₆haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or oxo; and HetC is a 5- or6-membered heteroaromatic ring containing from 1 to 4 heteroatomsindependently selected from N, O and S, wherein the heteroaromatic ringis optionally substituted with from 1 to 4 substituents each of which isindependently —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆haloalkyl, or oxo.
 3. The compound according to claim 2, or apharmaceutically acceptable salt thereof, wherein in R¹ is—(CH₂)₁₋₄-phenyl, wherein the phenyl is optionally substituted with from1 to 3 substituents each of which is independently (1) —C₁₋₄ alkyl,optionally mono-substituted with —OH, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl,—CN, —N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(c),—S(O)_(n)R^(c), or —SO₂N(R^(a)R^(b)), (2) —O—C₁₋₄ alkyl, (3) —C₁₋₄haloalkyl, (4) —O—C₁₋₄ haloalkyl, (5) —OH, (6) halo, (7) —CN, (8) —NO₂,(9) —N(R^(a)R^(b)), (10) —SR^(c), (11) —S(═O)R^(c), (12) —SO₂R^(c), (13)—N(R^(a))SO₂R^(c), (14) —SO₂N(R^(a)R^(b)), (15) —N(R^(a))C(═O)R^(b), or(16) —N(R^(a))CO₂R^(c).
 4. The compound according to claim 3, or apharmaceutically acceptable salt thereof, wherein R¹ is:

wherein X¹ and X² are each independently (1) —H, (2) methyl, (3) ethyl,(4) methoxy, (5) ethoxy, (6) —CF₃, (7) fluoro, (8) bromo, or (9) chloro.5. The compound according to claim 4, or a pharmaceutically acceptablesalt thereof, wherein R¹ is 4-fluorobenzyl.
 6. The compound according toclaim 1, or a pharmaceutically acceptable salt thereof, wherein: R² is—H or —C₁₋₄ alkyl; R³ is —H or —C₁₋₄ alkyl; R⁴ is: (1) —H, (2) —C₁₋₄alkyl optionally substituted with one of —OH, —O—C₁₋₄ alkyl, —O—C₁₋₄haloalkyl, —CN, —N(R^(a)R^(b)), —C(═O)N(R^(a)R^(b)), —C(═O)R^(a),—CO₂R^(c), —S(O)_(n)R^(c), —SO₂N(R^(a)R^(b)), —N(R^(a))—C(R^(b))═O,—N(R^(a))SO₂R^(b), or —N(R^(a))SO₂N(R^(a)R^(b)), (3)—C(═O)N(R^(a)R^(b)), (4) —R^(k), (5) —C₁₋₄ alkyl substituted with R^(k),(6) —C₁₋₄ alkyl-O-R^(k), or (7) —C₁₋₄ alkyl-O—C₁₋₄ alkyl-R^(k); and R⁵is —H.
 7. The compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁶ is: (1) —OH, (2) —O—C₁₋₄ alkyl, (3)—N(R^(u)R^(v)), (4) —O—C₁₋₄ haloalkyl, (5) —O—C₁₋₄ alkyl-aryl (6)—O—C₁₋₄ alkyl-HetB, or (7) —O—C₁₋₄ alkyl-HetC, wherein R^(u) is —H or—C₁₋₄ alkyl; R^(v) is —H, —C₁₋₄ alkyl, or cyclopropyl; HetB is a 5- or6-membered saturated ring containing a total of from 1 to 4 heteroatomsindependently selected from 1 to 4 N atoms, from 0 to 2 O atoms, andfrom 0 to 2 S atoms, wherein the saturated ring is optionallysubstituted with from 1 to 4 substituents each of which is independentlyhalogen, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl,or oxo; and HetC is a 5- or 6-membered heteroaromatic ring containing atotal of from 1 to 4 heteroatoms independently selected from 1 to 4 Natoms, from 0 to 2 O atoms, and from 0 to 2 S atoms, wherein theheteroaromatic ring is optionally substituted with from 1 to 3substituents each of which is independently —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, or oxo.
 8. A compound ofFormula (II), or a pharmaceutically acceptable salt thereof:

wherein: X^(′) and X^(2′) are each independently: (1) —H, (2) C₁₋₄alkyl, (2) —O—C₁₋₄ alkyl, (3) —C₁₋₄ haloalkyl, (4) —O—C₁₋₄ haloalkyl, or(5) halo; and R^(6′) is: (1) —OH, (2) —O—C₁₋₄ alkyl, or (3)—N(R^(u)R^(v)); wherein R^(u) is —H or —C₁₋₄ alkyl; and R^(v) is —C₁₋₄alkyl or cyclopropyl.
 9. A compound according to claim 8, or apharmaceutically acceptable salt thereof, wherein: wherein X^(1′) andX^(2′) are each independently: (1) —H, (2) methyl, (2) —OCH₃, (3) —CF₃,(4) —OCF₃, (5) chloro, (6) fluoro, or (7) bromo; and R^(6′) is: (1) —OH,(2) methoxy (3) ethoxy (4) —N(R^(u)R^(v)); wherein R^(u) is —H; andR^(v) is methyl, ethyl, or cyclopropyl.
 10. The compound according toclaim 8, which is a compound of Formula (III), or a pharmaceuticallyacceptable salt thereof:

wherein X^(1′) and X^(2′) are each independently —H or halo.
 11. Thecompound according to claim 10, or a pharmaceutically acceptable saltthereof, wherein X^(1′) and X^(2′) are each independently —H, fluoro,chloro, or bromo; and R^(6′) is: (1) —OH, (2) methoxy (3) ethoxy (4)—N(R^(u)R^(v)); wherein R^(u) is —H; and R^(v) is methyl, ethyl, orcyclopropyl.
 12. A compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, which is a compound of Formula (IV):

wherein R^(u) is —H or —C₁₋₆ alkyl; R^(v) is C₁₋₆ alkyl which issubstituted with 1 or 2 substituents each of which is independently: (1)C₃₋₈ cycloalkyl, (2) aryl, (3) a 5- or 6-membered saturated ormono-unsaturated heterocyclic ring containing from 1 to 4 heteroatomsindependently selected from N, O and S, (4) a 5- or 6-memberedheteroaromatic ring containing from 1 to 4 heteroatoms independentlyselected from N, O and S, or (5) a 9- or 10-membered fused bicyclicheterocycle containing from 1 to 4 heteroatoms independently selectedfrom N, O and S, wherein at least one of the rings is aromatic; wherein(A) each cycloalkyl is optionally substituted with from 1 to 3substituents, each of which is independently halo, —C₁₋₆ alkyl, or—O—C₁₋₆ alkyl; (B) each aryl is optionally substituted with from 1 to 5substituents each of which is independently (1) —C₁₋₆ alkyl, optionallysubstituted with from 1 to 3 substituents each of which is independently—OH, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —CN, —NO₂, —N(R^(a)R^(b)),—C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(c), S(O)_(n)R^(c),—SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(c),—N(R^(a))SO₂R^(c), —N(R^(a))SO₂N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)), or—N(R^(a))C(═O)N(R^(a)R^(b)), (2) —O—C₁₋₆ alkyl, optionally substitutedwith from 1 to 3 substituents each of which is independently —OH,—O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, —S(O)_(n)R^(c), —C(═O)N(R^(a)R^(b)),—SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(c),—N(R^(a))SO₂R^(c), —N(R^(a))SO₂N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)), or—N(R^(a))C(═O)N(R^(a)R^(b)), (3) —C₁₋₆ haloalkyl, (4) —O—C₁₋₆ haloalkyl,(5) —OH, (6) halo, (7) —CN, (8) —NO₂, (9) —N(R^(a)R^(b)), (10)—C(═O)N(R^(a)R^(b)), (11) —C(═O)R^(a), (12) —CO₂R^(c), (13) —SR^(c),(14) —S(═O)R^(c), (15) —SO₂R^(c), (16) —N(R^(a))SO₂R^(c), (17)—SO₂N(R^(a)R^(b)), (18) —N(R^(a))C(═O)R^(b), or (19) —N(R^(a))CO₂R^(c);(C) each saturated or mono-unsaturated heterocyclic ring is (i)optionally substituted with from 1 to 5 substituents each of which isindependently halogen, —C₁₋₆ alkyl, —C₁₋₆ haloalkyl, —O—C₁₋₆ alkyl,—O—C₁₋₆ haloalkyl, or oxo; and (ii) optionally substituted with 1 or 2substituents each of which is independently aryl or a 5- or 6-memberedheteroaromatic ring containing from 1 to 4 heteroatoms independentlyselected from N, O and S; and (D) each heteroaromatic ring or each fusedbicyclic heterocycle is (i) optionally substituted with from 1 to 7substituents each of which is independently halogen, —C₁₋₆ alkyl, —C₁₋₆haloalkyl, —O—C₁₋₆ alkyl, —O—C₁₋₆ haloalkyl, or oxo; and (ii) optionallysubstituted with 1 or 2 substituents each of which is independently arylor —C₁₋₆ alkyl-aryl; and R¹ is —H or —C₁₋₆ alkyl.
 13. The compoundaccording to claim 12, or a pharmaceutically acceptable salt thereof,wherein R^(v) is —C₁₋₄ alkyl mono-substituted with aryl; wherein thearyl is optionally substituted with from 1 to 4 substituents each ofwhich is independently (1) —C₁₋₄ alkyl, optionally mono-substituted with—OH, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl, —CN, —N(R^(a)R^(b)),—C(═O)N(R^(a)R^(b)), —C(═O)R^(a), —CO₂R^(c), —S(O)_(n)R^(c),—SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(c),—N(R^(a))SO₂R^(c), —N(R^(a))SO₂N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)), or—N(R^(a))C(═O)N(R^(a)R^(b)), (2) —O—C₁₋₄ alkyl, optionallymono-substituted with —OH, —O—C₁₋₄ alkyl, —O—C₁₋₄ haloalkyl,—S(O)_(n)R^(c), —N(R^(a))—CO₂R^(c), —C(═O)N(R^(a)R^(b)),—SO₂N(R^(a)R^(b)), —N(R^(a))C(═O)R^(b), —N(R^(a))CO₂R^(c),—N(R^(a))SO₂R^(c), —N(R^(a))SO₂N(R^(a)R^(b)), —OC(═O)N(R^(a)R^(b)), or—N(R^(a))C(═O)N(R^(a)R^(b)), (3) —C₁₋₄ haloalkyl, (4) —O—C₁₋₄ haloalkyl,(5) —OH, (6) halo, (7) —CN, (8) —NO₂, (9) —N(R^(a)R^(b)), (10) —SR^(c),(11) —S(═O)R^(c), (12) —SO₂R^(c), (13) —N(R^(a))SO₂R^(c), (14)—SO₂N(R^(a)R^(b)), (15) —N(R^(a))C(═O)R^(b), or (16) —N(R^(a))CO₂R^(c).14. The compound according to claim 13, or a pharmaceutically acceptablesalt thereof, wherein R^(v) is:

wherein X¹ and X² are each independently (1) —H, (2) methyl, (3) ethyl,(4) methoxy, (5) ethoxy, (6) —CF₃, (7) fluoro, (8) bromo, or (9) chloro.15. The compound according to claim 14, or a pharmaceutically acceptablesalt thereof, wherein R^(v) is 4-fluorobenzyl.
 16. The compoundaccording to claim 12, or a pharmaceutically acceptable salt thereof,wherein: R^(u) is —H; R⁵ is —H; R⁴ is: (1) —H, (2) —C₁₋₄ alkyloptionally substituted with one of —OH, —N(R^(a)R^(b)), or—C(═O)N(R^(a)R^(b)), (3) —C(═O)N(R^(a)R^(b)), (4) —(CH₂)₁₋₃—R^(k), (5)—(CH₂)₁₋₃—O—R^(k), or (6) —(CH₂)₁₋₃-O-(CH₂)₁₋₃—R^(k); R² is —H; and R¹is —C₁₋₄ alkyl
 17. A compound selected from the group consisting of:

and pharmaceutically acceptable salts thereof.
 18. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier.
 19. A method of inhibiting HIVintegrase in a subject in need thereof which comprises administering tothe subject a therapeutically effective amount of the compound accordingto claim 1, or a pharmaceutically acceptable salt thereof.
 20. A methodfor preventing or treating infection by HIV or for preventing, treatingor delaying the onset of AIDS in a subject in need thereof whichcomprises administering to the subject a therapeutically effectiveamount of the compound according to claim 1, or a pharmaceuticallyacceptable salt thereof. 21-22. (canceled)